WO2024218302A1

WO2024218302A1 - Nrp1-specific antisense oligonucleotides and their use in preventing and/or treating diseases

Info

Publication number: WO2024218302A1
Application number: PCT/EP2024/060724
Authority: WO
Inventors: André MAASKE; Julia FESTAG; Richard KLAR; Sven MICHEL; Frank Jaschinski
Original assignee: Secarna Pharmaceuticals Gmbh & Co. Kg
Priority date: 2023-04-21
Filing date: 2024-04-19
Publication date: 2024-10-24
Also published as: TW202442242A

Abstract

The present invention refers to an oligonucleotide comprising 10 to 25 nucleotides, wherein at least one of the nucleotides is modified, and the oligonucleotide hybridizes with pre-mRNA of neuropilin 1 (NRP1, CD304) of SEQ ID NO.366 (GRCh38p13_Chr 10_33177492-33336262-1) or mRNA of NRP1 of SEQ ID NO.367 (RefSeq ID NM_003873.6). The invention is further directed to a pharmaceutical composition comprising such oligonucleotide. The pharmaceutical composition and the oligonucleotide are for use in a method of preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder.

Description

P132364PC00 NRP1-specific antisense oligonucleotides and their use in preventing and/or treating diseases The present invention refers to oligonucleotides, in particular antisense oligonucleotides, comprising one or more modified nucleotides and hybridizing with neuropilin (NRP) such as NRP1 (CD304) pre-mRNA or mRNA. The oligonucleotides inhibit the expression of NRP, NRP mRNA and/or NRP pre-mRNA and are used for preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder. Technical background Neuropilin 1 (NRP1) is a multi-domain receptor involved in versatile signal transduction pathways that control cell migration, angiogenesis, cell survival, metastasis, and cell proliferation. Accordingly, NRP1 has been shown to serve as a co-receptor for a broad spectrum of growth factor receptors (Prud’homme et al., Oncotarget, 2012, 3(9): 921-939). Common binding partners for NRP1 are for example TGF-beta receptor I and II; vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR) and plexin (semaphorin receptor) (Prud’homme et al., Oncotarget, 2012, 3(9): 921-939). NRP1 expression has been reported in a wide variety of cells including cells of the immune system such as regulatory T cells (Tregs) (Prud’homme et al., Oncotarget, 2012, 3(9): 921-939). In general, neuropilins are overexpressed in several human tumor types, including carcinomas, melanoma, glioblastoma, leukemias and lymphomas. Overexpression of NRP1 correlates with more aggressive clinical tumor behavior (Prud’homme et al., Oncotarget, 2012, 3(9): 921-939). NRP1 has also been shown to be involved in the maturation of blood vessels. Former studies indicate that immature blood vessels depend on and respond to vascular endothelial growth factor (VEGF), which is a common ligand of NRP1 (Pan et al., Cancer Cell, 2007, 11(1), 53-67). Accordingly, inhibiting NRP1 expression would prevent abnormal blood vessel maturation and force them into an immature, VEGF dependent state. Therefore, a combined anti-NRP1 and anti-VEGF therapy is beneficial for the treatment of angiogenesis related ophthalmologic diseases and tumors. Functionally, NRP1 has been linked to immune inhibition. Several studies indicate that regulatory T cells (Tregs) express NRP1 on their surface (Hansen, W., Oncoimmunology, 2013, 2(2), e230399). VEGF producing tumor cells attract the NRP1-expressing Tregs due to the interaction of NRP1 and VEGF. While VEGF promotes tumor angiogenesis, the Tregs interfere with anti-tumor immune responses, e.g. by secreting immunosuppressive cytokines (Hansen, et al., Oncoimmunology, 2013, 2(2), e230399). Inhibition of NRP1 would prevent the infiltration of Tregs in the tumor microenvironment and therefore improve anti-tumor immune responses. Few antibodies have been developed to inhibit activity of NRP1: The anti-human NRP1 monoclonal antibody MNRP1685A (Genentech) inhibits specifically the VEGF binding domain of NRP1. This antibody was used in phase I clinical studies to treat patients suffering from advanced solid tumors (Weekes, et al., Investigational New Drug, 2014, 32(4), 653-660). However, relatively high concentrations and repetitive dosing of the antibody is needed to successfully block NRP1. Furthermore, the anti-VEGF antibody Aflibercept (Sanofi) is used as common therapy to treat diseases with pathological retinal angiogenesis, e.g. neovascular (wet) age-related macular degeneration (AMD), diabetic retinopathy and retinopathy of prematurity. However, application of Aflibercept is limited as it cannot inhibit binding of non-classical ligands to NRP1 which act as pro-angiogenic growth factors (e.g., TGF-beta, PDGF, semaphorines, HGF) and it shows only low activity against matured blood vessels. Relatively high concentrations and repetitive dosing via monthly intravitreal injections are required to successfully block NRP1 activity. As these therapies are very inconvenient for the patient, there is a need to develop improved therapies that enable less frequent applications. Furthermore, one small molecule EG00229 (Tocris) acts as a receptor antagonist of NRP1. EG00229 has been shown to inhibit binding of VEGF-A to the b1 domain of NRP1 at least in vitro. EG00229 enhances the chemo-sensitivity of A549 cells (Jarvis et al., Journal of Medicinal Chemistry, 2010, 53(5), 2215-2226), however, its clinical efficacy has not been determined in vivo so far. US 7,087,580 refers to oligonucleotides hybridizing with human neuropilin 1 comprising first generation modifications and mutations such as substitutions, insertions and deletions. NRP1 comprises several, partially overlapping binding sites for different ligands and co- receptors. Common approaches using a single antibody and/or a small molecule cannot or hardly block all interactions sites of such a multi-domain receptor. Antibody based therapies would require administering more than one antibody. Accordingly, an agent which is safe and effective in inhibiting simultaneously the complete functions mediated by a receptor such as NRP1 would be an important addition for the treatment of patients suffering from diseases or conditions affected for example by the activity of NRP1 and its pro-angiogenic ligands. Oligonucleotides of the present invention are very successful in the inhibition of the expression and activity of NRP1, respectively. The mode of action of an oligonucleotide differs from the mode of action of an antibody or small molecule, and oligonucleotides are highly advantageous regarding for example (i) the blocking of multiple functions and activities, respectively, of a target, (ii) the penetration of tumor tissue in solid tumors due to their small molecular size, (iii) the combination of oligonucleotides with each other or an antibody or a small molecule, and (iv) the inhibition of intracellular effects which are not accessible for an antibody or effects not inhibitable via a small molecule. Oligonucleotides of the present invention are advantageous in comparison to previous generations of oligonucleotides due to their higher stability, stronger target affinity and potency and due to their independence from delivery reagents to achieve target suppression in cells. Summary The present invention refers to an oligonucleotide comprising or consisting of 10 to 25 nucleotides, at least one nucleotide having a modification selected from the group consisting of a bridged nucleic acid such as LNA, ENA, cET, a 2'Fluoro modified nucleotide, a 2´O-Methyl modified nucleotide, a 2´O-Methoxyethyl modified nucleotide, a FANA and a combination thereof, and wherein the oligonucleotide hybridizes with a transcript or an mRNA of neuropilin 1 (NRP1) of SEQ ID NO.367 and/or with pre-mRNA of NRP1 of SEQ ID NO.366. The modification is for example located in a sequence of the 5´-end and/or 3´-end of the oligonucleotide such as a sequence of 5 nucleotides. The oligonucleotide of the present invention hybridizes outside a hybridizing active region or within a hybridizing active region of position 6450-6749, 12150-12449, 134250- 134549, 36150-36449, 17550-17849, 138750-139049, 32550-32849 or a combination thereof. The oligonucleotide comprises or consists of for example SEQ ID NO.5, SEQ ID NO.120, SEQ ID NO.19, SEQ ID NO.163, SEQ ID NO.129, SEQ ID NO.364, SEQ ID NO.330, SEQ ID NO.158, SEQ ID NO.156, or a combination thereof. The oligonucleotide is for example selected from the group consisting of +A*+T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15091HI; SEQ ID NO:5), +T*+C*+G*T*T*G*G*A*A*A*T*G*C*C*A*T*+G*+C*+A (A15219HI; SEQ ID NO:120), +T*+A*+C*A*T*G*G*T*A*A*C*G*C*+C*+T*+T (A15108HI; SEQ ID NO:19), +A*+T*+A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G (A15486HI; SEQ ID NO:5), +A*+T*A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G (A15487HI; SEQ ID NO:5), +G*+G*+T*T*A*T*T*G*A*C*T*G*C*T*C*T*+C*+T*+A (A15262HI; SEQ ID NO:163), +G*+T*+T*T*C*C*T*T*A*G*C*T*T*A*G*T*+G*+C*+C (A15228HI; SEQ ID NO:129), +A*+A*T*+A*T*T*T*A*G*G*T*C*C*+A*G*+C*+G (A15466HI; SEQ ID NO:364), +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+G (A15430HI; SQE ID NO:330), +T*+A*+G*G*T*A*C*G*A*G*C*A*T*+C*+G*+G (A15257HI; SQE ID NO:158), +A*+A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15465HI; SEQ ID NO:364), +A*T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15473HI; SEQ ID NO:5), +T*+T*+C*G*T*A*T*T*T*A*A*A*C*T*C*+T*+A*+C (A15255HI; SEQ ID NO:156) and a combination thereof, wherein + indicates an LNA nucleotide and * indicates a phosphorothioate (PTO) linkage or a mesyl-phosphoramidate or a combination thereof between the nucleotides. Moreover, the oligonucleotide of the present invention has for example 80 to 99 %, 85 to 98 %, 90 to 95 or 93 % sequence identity to any one of the oligonucleotides of SEQ ID NO.1 – SEQ ID NO.364. It comprises or consists of for example at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 nucleotides of any one of the oligonucleotides of SEQ ID NO.1 – SEQ ID NO.364. The oligonucleotide of the present invention inhibits the expression of NRP1, a NRP1 mRNA, a NRP1 pre- mRNA or a combination thereof for example at a nanomolar or micromolar concentration. The present invention further refers to a pharmaceutical composition comprising an oligonucleotide of the present invention and a pharmaceutically acceptable carrier, excipient, dilutant, stimulant such as an adjuvant, or a combination thereof. Optionally, the pharmaceutical composition further comprises a therapeutically active agent such as a chemotherapeutic, another oligonucleotide, an antagonistic protein, an antibody and/or a small molecule being effective in treating a tumor or an ophthalmic disease. The pharmaceutical composition and the oligonucleotide of the present invention, respectively, inhibit for example the activity of a receptor such as a growth receptor selected from the group consisting of TGF-beta receptor I (TβRI), TGF-beta receptor II (TβRII), VEGF, HGF, PDGF and SEMA3 (Plexin), or a combination thereof, or inhibit for example the activity of a signal transduction factor such as p38MAPK, ERK1, ERK2, PI3K, Akt, NF-κB, pSMAD2, pSMAD3, Src, Pyk2, FAK, p-p130Cas, or a combination thereof. Further, the pharmaceutical composition or the oligonucleotide of the present invention inhibits for example the immigration and/or function of a Treg cell, a myeloid- derived suppressor cell (MDSC), or any other immune cell, and a combination thereof into a tumor. The pharmaceutical composition or the oligonucleotide of the present invention is for use in preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder. The ophthalmic disease is for example an angiogenic eye disease such as age related macular disease (AMD), diabetic retinopathy (DME), retinopathy of prematurity (Retinopathia praematurorum) or corneal neovascularization. The cancer is for example bladder carcinoma, breast cancer, colorectal carcinoma, lung cancer, malignant melanoma, mesothelioma, lymphoma, skin cancer, bone cancer, prostate cancer, hepatocarcinoma, brain cancer, cancer of the larynx, liver, gall bladder, pancreas, testicular, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, neuroblastoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, liposarcoma, leukemia, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, meningioma, acute and chronic lymphocytic and granulocytic tumors, acute and chronic myeloid leukemia, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, intestinal ganglioneuromas, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, polycythaemia vera, adenocarcinoma, anaplastic astrocytoma, glioblastoma multiforma, leukemia, or epidermoid carcinoma. The pharmaceutical composition or the oligonucleotide of the present invention is for example administered locally or systemically. All documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. Description of figures Fig.1 shows RefSeq ID NM_003873.6 of NRP1 mRNA (SEQ ID NO.367). Fig.2 shows screening results of human NRP1-specific ASOs in SKOV-3 cells. Fig.3 depicts screening results of human NRP1-specific ASOs in U87-MG cells. Fig.4 shows screening results of human NRP1-specific ASOs in Panc1 cells. Fig.5 depicts screening results of human NRP1-specific ASOs in CD4+ T cells. Fig.6 depicts concentration-dependent NRP1 mRNA knockdown by selected NRP1- specific ASOs in SKOV-3 cells. Fig.7 depicts concentration-dependent NRP1 mRNA knockdown by selected NRP1- specific ASOs in CD4+ T cells. Fig.8 shows monitoring of serological indicators for acute toxicity of selected human NRP1-specific ASOs in Balb/c mice. Fig.9 depicts a NRP1 mRNA knockdown by selected NRP1-specific ASOs in SKOV-3 cells. In order to compare the knockdown efficacy of ASOs with the same underlying sequence but different LNA-modification pattern, SKOV-3 cells were treated with ASOs (A15486HI (SEQ ID NO.5), A15479HI (SEQ ID NO.5), A15487HI (SEQ ID NO.5), A15091HI (SEQ ID NO.5) and A15478HI (SEQ ID NO.5) at a concentration of 5 µM for three days without the addition of a transfection reagent. Cells were lysed after the three days treatment period, NRP1 and HPRT1 mRNA expression was analyzed using the QuantiGene Singleplex assay (ThermoFisher) and the NRP1 expression values were normalized to HPRT1 values and compared to mock-treated samples. Fig.10 shows a concentration-dependent NRP1 mRNA knockdown by selected NRP1- specific ASOs (A15091HI (SEQ ID NO.5), A15486HI (SEQ ID NO.5), and A15487HI (SEQ ID NO.5)) in Panc1 cells. Fig.11 depicts NRP1 mRNA knockdown by selected NRP1-specific ASOs (A15091HI (SEQ ID NO.5), A15486HI (SEQ ID NO.5), and A15487HI (SEQ ID NO.5)) in SKOV-3 cells. Detailed description The present invention provides human-, monkey-, murine- and rat-specific oligonucleotides which hybridize with mRNA sequences of neuropilin such as NRP1 of human mouse and/or monkey and/or rat and inhibit the expression and activity, respectively, of NRP1. NRP1 as a multi-domain receptor binds to several different types of ligands and receptors relevant for cell migration, angiogenesis, cell survival, metastasis and cell proliferation. Many ligands of NRP1 act as pro-angiogenic growth factors. Therefore, inhibition of expression of NRP1 allows targeting a broad spectrum of different activities of NRP1 simultaneously, thereby significantly increasing the feasibility of a successful therapy. They represent an interesting and highly efficient tool for use in a method of preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder. In the following, the elements of the present invention will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. Throughout this specification and the claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The terms "a" and "an" and "the" and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as", “for example”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. The term “about” refers to a figure indicated and +/- 10 % of this figure. Oligonucleotides of the present invention are for example antisense oligonucleotides consisting of or comprising 10 to 25 nucleotides, 15 to 20 nucleotides, 12 to 18 nucleotides, or 14 to 17 nucleotides. The oligonucleotides for example consist of or comprise 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 25 nucleotides. The oligonucleotides of the present invention comprise for example at least one nucleotide which is modified. The modified nucleotide is for example a bridged nucleotide such as a locked nucleic acid (LNA, e.g., 2´,4´-LNA such as beta-D-LNA and/or alpha-L-LNA), cET, ENA, a 2`Fluoro modified nucleotide, a 2`O-Methyl, a 2’O-Methoxyethyl modified nucleotide or a combination thereof. The oligonucleotide of the present invention comprises nucleotides having for example one or more, two or more, three or more or four or more of the same or different modifications. Further, the oligonucleotide of the present invention comprises optionally a modified phosphate backbone, wherein the phosphate is, for example, a phosphorothioate, methylphosphonate, mesyl-phosphoramidate (MsPA; e.g., WO 2021/030778) or a combination thereof. Optionally the cytosines of the oligonucleotide comprises one or more methyl group(s). A mesyl-phosphoramidate for example is introduced as a stereorandom and/or stereoselective linkage in the gap and/or one or both wings of a gapmer oligonucleotide. Optionally all phosphate or phosphorothioate linkages of the oligonucleotide are replaced by mesyl-phosphoramidate, or all phosphate or phosphorothioate linkages of the gap or all phosphate or phosphorothioate linkages of one or both wings are replaced by mesyl- phosphoramidate. For example 1 to 5 phosphate or phosphorothioate linkages of the gap are replaced by mesyl-phosphoramidate and/or 3 to 5 phosphate or phosphorothioate linkages near the 5´-side of the gap are replaced by mesyl-phosphoramidate. The mesyl- phosphoramidate is for example introduced into the oligonucleotide by means of a Staudinger reaction, e.g., between methanesulfonyl azide (MsN3, 0.5M solution in 1:1 acetonitrile/toluene) and the trivalent phosphite intermediate produced upon phosphoramidite coupling (as described for example in Anderson B.A. et al., Nucleic Acid Research, 2021, Vol.49, No. 16, 9026-9041). Also a phosphorothioate introduces for example a stereorandom and/or a stereoselective linkage in the gap and/or one or both wings of a gapmer oligonucleotide. According to the present invention, “gapmer” means an oligonucleotide having a central region comprising a plurality of nucleosides that support RNase H cleavage positioned between a 5’-region and a 3’-region. The positions of the central region refer to the order of the nucleosides of the central region and are counted starting from the 5’-end of the central region. Thus, the 5’-most nucleoside of the central region is at position 1 of the central region. The “central region” may be referred to as a “gap”, and the “5’-region” and “3’-region” may be referred to as “wings”. The oligonucleotide of the present invention is for example an antisense oligonucleotide (e.g., DNA), siRNA, or miRNA. “Reducing” according to the present invention includes inhibiting an effect such as expression in different percentages and amounts, respectively. The present invention refers to the provision of an oligonucleotide such as an antisense oligonucleotide, mediating the limitation of available NRP1 mRNA for protein expression. In order to limit protein expression, the oligonucleotide requires the presence of a complementary nucleic acid sequence representing a hybridization target, which allows the formation of heteroduplexes. The oligonucleotides of the present invention hybridize with pre-mRNA of SEQ ID NO.366 (GRCh38p13_Chr 10_33177492-33336262- 1) and/or mRNA of SEQ ID NO.367 (RefSeq ID NM_003873.6). GRCh38p13_Chr 10_33177492-33336262-1 and RefSeq ID NM_003873.6 specify the exact version of the sequences. The formation of a heteroduplex between the oligonucleotide and the target RNA leads to recruitment of enzymes such as RNaseH leading to degradation or inactivation of the target RNA or termination of transcription, and thus, limits the amount of available NRP1 mRNA for protein expression. The oligonucleotide of the present invention comprises one or more, two or more, three or more, or four or more modified nucleotide(s) for example at the 3´- and/or 5´- end of the oligonucleotide and/or at any position within the oligonucleotide. The modified nucleotides follow for example in a row of 1, 2, 3, 4, 5, or 6 modified nucleotides, or a modified nucleotide is combined with one or more, two or more, three or more, or four or more unmodified nucleotides. The modified nucleotides are for example in a sequence of 5 nucleotides at the 3´- and/or 5´- end of the oligonucleotide. This sequence needs not to start with the first nucleotide of the 3´- or 5´- end of the oligonucleotide. The following Table 1 presents embodiments of oligonucleotides comprising modified nucleotides for example LNA which are indicated by (+) and phosphorothioate (PTO) indicated by (*). Alternatively, in the oligonucleotides of Table 1 one or more PTO linkages are replaced by mesyl- phosphoramidate. The oligonucleotides consisting of or comprising the sequences of Table 1 may comprise any other modified nucleotide and any other combination of modified and unmodified nucleotides. Oligonucleotides of Table 1 hybridize with mRNA of human, monkey, mouse and/or rat NRP1, preferably human NRP1: Seq Name Antisense Sequence 5’-3’ Antisense Sequence 5’-3’ with PTO (*) and LNA Position on pre- ID (ASO ID) (+) mRNA (GRCh38p13_10_33 177492-33336262_- 1)** 1 A15087HI TCTGATCGTGTAGCG +T*+C*+T*G*A*T*C*G*T*G*T*A*+G*+C*+G 82429_82443 2 A15088HI TGATCGTCGAGAGCC +T*+G*+A*T*C*G*T*C*G*A*G*A*+G*+C*+C 84119_84133 3 A15089HI GGCGTTAATAACTCG +G*+G*+C*G*T*T*A*A*T*A*A*C*+T*+C*+G 114263_114277 4 A15090HI TTGGACGAGAATGCTA +T*+T*+G*G*A*C*G*A*G*A*A*T*G*+C*+T*+A 3189_3204 5 A15091HI ATATTTAGGTCCAGCG +A*+T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6713 6 A15092HI AGTTCGATGTACATAC +A*+G*+T*T*C*G*A*T*G*T*A*C*A*+T*+A*+C 9942_9957 7 A15093HI GTCGCAACGTTTCCTG +G*+T*+C*G*C*A*A*C*G*T*T*T*C*+C*+T*+G 67280_67295 8 A15095HI GTAACGTGGCAATTCG +G*+T*+A*A*C*G*T*G*G*C*A*A*T*+T*+C*+G 70457_70472 9 A15096HI TAAGGTCTAACCTCGG +T*+A*+A*G*G*T*C*T*A*A*C*C*T*+C*+G*+G 73841_73856 10 A15097HI AGCACCGATGTGACGT +A*+G*+C*A*C*C*G*A*T*G*T*G*A*+C*+G*+T 75724_75739 11 A15098HI CTCTGTCGGTGAACTA +C*+T*+C*T*G*T*C*G*G*T*G*A*A*+C*+T*+A 80321_80336 12 A15099HI ATTAGTGTCGTATGAG +A*+T*+T*A*G*T*G*T*C*G*T*A*T*+G*+A*+G 85422_85437 13 A15100HI CACGCGTTCTTACAAG +C*+A*+C*G*C*G*T*T*C*T*T*A*C*+A*+A*+G 110590_110605 14 A15102HI GCCACATCGTTTACTC +G*+C*+C*A*C*A*T*C*G*T*T*T*A*+C*+T*+C 120213_120228 15 A15103HI TAATCGACACTGCGGA +T*+A*+A*T*C*G*A*C*A*C*T*G*C*+G*+G*+A 129192_129207 16 A15104HI ATTGAACGAACGCATC +A*+T*+T*G*A*A*C*G*A*A*C*G*C*+A*+T*+C 130003_130018 17 A15105HI CGTATCTGCCGAGTAG +C*+G*+T*A*T*C*T*G*C*C*G*A*G*+T*+A*+G 133045_133060 18 A15106HI TCGTATCTGCCGAGTA +T*+C*+G*T*A*T*C*T*G*C*C*G*A*+G*+T*+A 133046_133061 19 A15108HI TACATGGTAACGCCTT +T*+A*+C*A*T*G*G*T*A*A*C*G*C*+C*+T*+T 134278_134293 20 A15109HI CGACGCATGGCACACA +C*+G*+A*C*G*C*A*T*G*G*C*A*C*+A*+C*+A 137700_137715 21 A15110HI ACCGTTTAACCGTGAC +A*+C*+C*G*T*T*T*A*A*C*C*G*T*+G*+A*+C 139201_139216 22 A15111HI GTAGGACGACACCATT +G*+T*+A*G*G*A*C*G*A*C*A*C*C*+A*+T*+T 139705_139720 23 A15113HI GTTAATCTACGACAAG +G*+T*+T*A*A*T*C*T*A*C*G*A*C*+A*+A*+G 146184_146199 24 A15115HI GTTGGACGAGAATGCTA +G*+T*+T*G*G*A*C*G*A*G*A*A*T*G*+C*+T*+A 3189_3205 25 A15116HI TTCTCAATCGCTAGGTG +T*+T*+C*T*C*A*A*T*C*G*C*T*A*G*+G*+T*+G 4071_4087 26 A15117HI ATCGGATCAAAGCAACG +A*+T*+C*G*G*A*T*C*A*A*A*G*C*A*+A*+C*+G 4717_4733 27 A15119HI AGGCGTGACCACTAGAT +A*+G*+G*C*G*T*G*A*C*C*A*C*T*A*+G*+A*+T 5594_5610 28 A15120HI AGCTAGTTTACTACACC +A*+G*+C*T*A*G*T*T*T*A*C*T*A*C*+A*+C*+C 7798_7814 29 A15121HI CTAACGAAGTATCCACC +C*+T*+A*A*C*G*A*A*G*T*A*T*C*C*+A*+C*+C 9480_9496 30 A15122HI TTGCGCACTCCTTATAC +T*+T*+G*C*G*C*A*C*T*C*C*T*T*A*+T*+A*+C 66440_66456 A15123HI TCTATCGAAACAAGCTT +T*+C*+T*A*T*C*G*A*A*A*C*A*A*G*+C*+T*+T 67174_67190 A15124HI AGACTAACAGATACGTA +A*+G*+A*C*T*A*A*C*A*G*A*T*A*C*+G*+T*+A 67717_67733 A15125HI CACACCGGAAACCTCAA +C*+A*+C*A*C*C*G*G*A*A*A*C*C*T*+C*+A*+A 68291_68307 A15126HI TGAATACACGTGATAGT +T*+G*+A*A*T*A*C*A*C*G*T*G*A*T*+A*+G*+T 69620_69636 A15127HI TGACAGCGACTATGCTA +T*+G*+A*C*A*G*C*G*A*C*T*A*T*G*+C*+T*+A 70356_70372 A15128HI GTAACGTGGCAATTCGC +G*+T*+A*A*C*G*T*G*G*C*A*A*T*T*+C*+G*+C 70456_70472 A15129HI GGTAACGTGGCAATTCG +G*+G*+T*A*A*C*G*T*G*G*C*A*A*T*+T*+C*+G 70457_70473 A15130HI ACATATCGGCTATCCAT +A*+C*+A*T*A*T*C*G*G*C*T*A*T*C*+C*+A*+T 70639_70655 A15131HI ACACAGTATAGTACGCC +A*+C*+A*C*A*G*T*A*T*A*G*T*A*C*+G*+C*+C 71688_71704 A15132HMI GTGAAAGGTAATTCGTA +G*+T*+G*A*A*A*G*G*T*A*A*T*T*C*+G*+T*+A 71865_71881 A15134HI GTTAATTGTTCCTCGAT +G*+T*+T*A*A*T*T*G*T*T*C*C*T*C*+G*+A*+T 75045_75061 A15136HI CTCTTATCCGTCTCGTG +C*+T*+C*T*T*A*T*C*C*G*T*C*T*C*+G*+T*+G 76807_76823 A15137HI CGAGACCTTAGCCTAGC +C*+G*+A*G*A*C*C*T*T*A*G*C*C*T*+A*+G*+C 76865_76881 A15138HI ACAATATGGTGTGGACT +A*+C*+A*A*T*A*T*G*G*T*G*T*G*G*+A*+C*+T 78359_78375 A15139HI CCTGTCCTGATCATCGA +C*+C*+T*G*T*C*C*T*G*A*T*C*A*T*+C*+G*+A 78469_78485 A15140HI TCAGGTTCGCATTATAT +T*+C*+A*G*G*T*T*C*G*C*A*T*T*A*+T*+A*+T 80608_80624 A15141HI CGTGAACCTATCTTCTC +C*+G*+T*G*A*A*C*C*T*A*T*C*T*T*+C*+T*+C 82336_82352 82377_82393 A15142HI CAAGGTAGACGTCTCAT +C*+A*+A*G*G*T*A*G*A*C*G*T*C*T*+C*+A*+T 83459_83475 A15143HI AAGCACAACGACGTGGA +A*+A*+G*C*A*C*A*A*C*G*A*C*G*T*+G*+G*+A 84073_84089 A15144HI TCTGCTTTGCGTGTCAA +T*+C*+T*G*C*T*T*T*G*C*G*T*G*T*+C*+A*+A 86990_87006 A15145HI GCCGACTCCTTCCTTAT +G*+C*+C*G*A*C*T*C*C*T*T*C*C*T*+T*+A*+T 112045_112061 A15146HI ATTCTAGGTCGTGTTTG +A*+T*+T*C*T*A*G*G*T*C*G*T*G*T*+T*+T*+G 113961_113977 A15147HI TACTGTCCTAATCATCG +T*+A*+C*T*G*T*C*C*T*A*A*T*C*A*+T*+C*+G 114198_114214 A15148HI TCGTAACGTGTTAGCCT +T*+C*+G*T*A*A*C*G*T*G*T*T*A*G*+C*+C*+T 116868_116884 A15149HI ATCGTAACGTGTTAGCC +A*+T*+C*G*T*A*A*C*G*T*G*T*T*A*+G*+C*+C 116869_116885 A15150HI TATCGTAACGTGTTAGC +T*+A*+T*C*G*T*A*A*C*G*T*G*T*T*+A*+G*+C 116870_116886 A15152HI AACCGTCACCAGATTAA +A*+A*+C*C*G*T*C*A*C*C*A*G*A*T*+T*+A*+A 119021_119037 A15153HI TAGAAATTACGCACGTC +T*+A*+G*A*A*A*T*T*A*C*G*C*A*C*+G*+T*+C 120437_120453 A15154HI GGAGTAGCCTATCACTA +G*+G*+A*G*T*A*G*C*C*T*A*T*C*A*+C*+T*+A 121509_121525 A15155HI TTTATCCTGATCCGAGC +T*+T*+T*A*T*C*C*T*G*A*T*C*C*G*+A*+G*+C 121719_121735 A15157HI ACGACTGAGTGGTATCT +A*+C*+G*A*C*T*G*A*G*T*G*G*T*A*+T*+C*+T 123201_123217 A15158HI GTTGCAGACGCATGAAT +G*+T*+T*G*C*A*G*A*C*G*C*A*T*G*+A*+A*+T 125068_125084 A15159HI GTGCTTGTTCGGTGGTG +G*+T*+G*C*T*T*G*T*T*C*G*G*T*G*+G*+T*+G 126252_126268 A15160HI AATCCGAGGAGAGTCAT +A*+A*+T*C*C*G*A*G*G*A*G*A*G*T*+C*+A*+T 128901_128917 A15162HI CGACACTGCGGACCGAA +C*+G*+A*C*A*C*T*G*C*G*G*A*C*C*+G*+A*+A 129187_129203 A15163HI AATTGAACGAACGCATC +A*+A*+T*T*G*A*A*C*G*A*A*C*G*C*+A*+T*+C 130003_130019 A15164HI TCCTAAATCAGCATCGC +T*+C*+C*T*A*A*A*T*C*A*G*C*A*T*+C*+G*+C 130092_130108 A15165HI GAGTTACGGCACATGGA +G*+A*+G*T*T*A*C*G*G*C*A*C*A*T*+G*+G*+A 131977_131993 A15166HI TCGTATCTGCCGAGTAG +T*+C*+G*T*A*T*C*T*G*C*C*G*A*G*+T*+A*+G 133045_133061 A15167HI CATGCGGAGTTACAAGC +C*+A*+T*G*C*G*G*A*G*T*T*A*C*A*+A*+G*+C 133452_133468 A15168HI GGTTCATGGAATAGTAC +G*+G*+T*T*C*A*T*G*G*A*A*T*A*G*+T*+A*+C 134718_134734 A15169HI GTTTGTAACTCGCTGCC +G*+T*+T*T*G*T*A*A*C*T*C*G*C*T*+G*+C*+C 135077_135093 A15170HI GACGACGCATGGCACAC +G*+A*+C*G*A*C*G*C*A*T*G*G*C*A*+C*+A*+C 137701_137717 A15171HI TGATCGACAGCAAACCG +T*+G*+A*T*C*G*A*C*A*G*C*A*A*A*+C*+C*+G 139177_139193 A15172HI GAAGGCCACCGTTTAAC +G*+A*+A*G*G*C*C*A*C*C*G*T*T*T*+A*+A*+C 139207_139223 A15173HI TGTAGGACGACACCATT +T*+G*+T*A*G*G*A*C*G*A*C*A*C*C*+A*+T*+T 139705_139721 A15174HI TCAACTGAACGGTGACT +T*+C*+A*A*C*T*G*A*A*C*G*G*T*G*+A*+C*+T 142075_142091 A15175HI GTCGATTAATTTAAGTA +G*+T*+C*G*A*T*T*A*A*T*T*T*A*A*+G*+T*+A 143247_143263 A15176HI ATGCAGCCGAAGTGAAC +A*+T*+G*C*A*G*C*C*G*A*A*G*T*G*+A*+A*+C 143993_144009 A15177HI CGTGCACATAGAGAATT +C*+G*+T*G*C*A*C*A*T*A*G*A*G*A*+A*+T*+T 144645_144661 A15178HI CGTTAACAAGTAGTTCC +C*+G*+T*T*A*A*C*A*A*G*T*A*G*T*+T*+C*+C 146368_146384 A15181HI AGCGTAACACAGACTTC +A*+G*+C*G*T*A*A*C*A*C*A*G*A*C*+T*+T*+C 150411_150427 A15182HI TTCGTTAGAACTTGTTG +T*+T*+C*G*T*T*A*G*A*A*C*T*T*G*+T*+T*+G 151847_151863 A15183HI TAGTGTGCGTTAGTTTG +T*+A*+G*T*G*T*G*C*G*T*T*A*G*T*+T*+T*+G 152763_152779 A15184HI GATTCGTACATATGGTG +G*+A*+T*T*C*G*T*A*C*A*T*A*T*G*+G*+T*+G 152817_152833 A15185HI TAAGGTATGTAGGACGG +T*+A*+A*G*G*T*A*T*G*T*A*G*G*A*+C*+G*+G 154440_154456 A15186HMI GCCTAATTACCTGGTAC +G*+C*+C*T*A*A*T*T*A*C*C*T*G*G*+T*+A*+C 155098_155114 A15187H ATCCGAGAGGAACGCTT +A*+T*+C*C*G*A*G*A*G*G*A*A*C*G*+C*+T*+T 1702_1718 A15188H TAAGCGATCCGAAGAGC +T*+A*+A*G*C*G*A*T*C*C*G*A*A*G*+A*+G*+C 1790_1806 A15189H AGAATCTAAGCGATCCG +A*+G*+A*A*T*C*T*A*A*G*C*G*A*T*+C*+C*+G 1796_1812 A15190H TATCGTTGCGAAAAGCG +T*+A*+T*C*G*T*T*G*C*G*A*A*A*A*+G*+C*+G 345_361 A15191H CCATGTGTTTCGTAGTC +C*+C*+A*T*G*T*G*T*T*T*C*G*T*A*+G*+T*+C 65534_65550 A15192H ATTTCTAGCCGGTCGTA +A*+T*+T*T*C*T*A*G*C*C*G*G*T*C*+G*+T*+A 72581_72597 A15193H TATCGCGCTGTCGGT +T*+A*+T*C*G*C*G*C*T*G*T*C*+G*+G*+T 79878_79892 A15194H CTTTTGCTATCGCGCTG +C*+T*+T*T*T*G*C*T*A*T*C*G*C*G*+C*+T*+G 79883_79899 A15195H CCGACAGCCGTGACAAA +C*+C*+G*A*C*A*G*C*C*G*T*G*A*C*+A*+A*+A 109995_110011 A15196H CTAACGTCGATCTTGTA +C*+T*+A*A*C*G*T*C*G*A*T*C*T*T*+G*+T*+A 110064_110080 A15197H GGAGCTAACGTCGATC +G*+G*+A*G*C*T*A*A*C*G*T*C*G*+A*+T*+C 110069_110084 A15198H TTGCAGGCTTGATTCGG +T*+T*+G*C*A*G*G*C*T*T*G*A*T*T*+C*+G*+G 114474_114490 A15199H GCAACCGTATACTTCAA +G*+C*+A*A*C*C*G*T*A*T*A*C*T*T*+C*+A*+A 114518_114534 A15200H TCTTGCAACCGTATACT +T*+C*+T*T*G*C*A*A*C*C*G*T*A*T*+A*+C*+T 114522_114538 A15201H TTCGCCTTGCGTTTGCT +T*+T*+C*G*C*C*T*T*G*C*G*T*T*T*+G*+C*+T 122860_122876 A15202H TGAATCGCGTGGAGAGA +T*+G*+A*A*T*C*G*C*G*T*G*G*A*G*+A*+G*+A 128600_128616 A15203H TCCTGATGAATCGCGTG +T*+C*+C*T*G*A*T*G*A*A*T*C*G*C*+G*+T*+G 128606_128622 A15204H CTGAGTGTGCCGACGTG +C*+T*+G*A*G*T*G*T*G*C*C*G*A*C*+G*+T*+G 149906_149922 A15205H TCTGGTAGCGCAGTTTG +T*+C*+T*G*G*T*A*G*C*G*C*A*G*T*+T*+T*+G 149926_149942 A15206H ATCGTACTCCTCTGGCT +A*+T*+C*G*T*A*C*T*C*C*T*C*T*G*+G*+C*+T 149943_149959 A15207H CCTTCGTATCCTGGCGT +C*+C*+T*T*C*G*T*A*T*C*C*T*G*G*+C*+G*+T 155903_155919 A15208H ATGCCTCCGAATAAGTA +A*+T*+G*C*C*T*C*C*G*A*A*T*A*A*+G*+T*+A 156169_156185 A15209H CGGCCATACTCATTGAA +C*+G*+G*C*C*A*T*A*C*T*C*A*T*T*+G*+A*+A 156321_156337 A15210H CACATGAGTCCGATGGT +C*+A*+C*A*T*G*A*G*T*C*C*G*A*T*+G*+G*+T 156364_156380 A15211H CCACACGGAATACGCTT +C*+C*+A*C*A*C*G*G*A*A*T*A*C*G*+C*+T*+T 156551_156567 A15212H TCTTTGCCTATGCACGA +T*+C*+T*T*T*G*C*C*T*A*T*G*C*A*+C*+G*+A 156671_156687 A15213H GACAGTATTGCTTCGTA +G*+A*+C*A*G*T*A*T*T*G*C*T*T*C*+G*+T*+A 156754_156770 A15214H ACGAGGTTTAGTACAAC +A*+C*+G*A*G*G*T*T*T*A*G*T*A*C*+A*+A*+C 156795_156811 A15215H TGAGACGTCTAGCAATG +T*+G*+A*G*A*C*G*T*C*T*A*G*C*A*+A*+T*+G 158027_158043 A15216H ACTGTCTCGTCTATGAT +A*+C*+T*G*T*C*T*C*G*T*C*T*A*T*+G*+A*+T 158075_158091 A15217HI ATGTTGGCCTCTAGATT +A*+T*+G*T*T*G*G*C*C*T*C*T*A*G*A*T*+T*+ 11165_11183 GG G*+G A15218HI ACAACCTCGTAATACTC +A*+C*+A*A*C*C*T*C*G*T*A*A*T*A*C*+T*+C*+ 12172_12189 A A A15219HI TCGTTGGAAATGCCATG +T*+C*+G*T*T*G*G*A*A*A*T*G*C*C*A*T*+G*+ 12282_12300 CA C*+A A15220HI CCATAAGACACTACTAA +C*+C*+A*T*A*A*G*A*C*A*C*T*A*C*T*A*+A*+ 12705_12723 CT C*+T A15221HI AATAAGCTGGTAACGTT +A*+A*+T*A*A*G*C*T*G*G*T*A*A*C*+G*+T*+T 13391_13407 A15222HI CGTGACATAGCAGTCTA +C*+G*+T*G*A*C*A*T*A*G*C*A*G*T*C*+T*+A* 14399_14416 T +T A15223HI GACTTGGAATCGTGACT +G*+A*+C*T*T*G*G*A*A*T*C*G*T*G*A*C*+T*+ 14519_14537 AT A*+T A15224HI ATCTTGCATAATAGCTG +A*+T*+C*T*T*G*C*A*T*A*A*T*A*G*C*T*+G*+ 14576_14594 CC C*+C A15225HI CCTCAACTCTTCATATAC +C*+C*+T*C*A*A*C*T*C*T*T*C*A*T*A*T*+A*+C 15563_15581 C *+C A15226HI TTCACCTCAACTCTTCAT +T*+T*+C*A*C*C*T*C*A*A*C*T*C*T*T*C*+A*+T 15567_15585 A *+A A15227HI TCTCTCTCCAGACAATCC +T*+C*+T*C*T*C*T*C*C*A*G*A*C*A*A*T*+C*+C 15898_15916 G *+G A15228HI GTTTCCTTAGCTTAGTGC +G*+T*+T*T*C*C*T*T*A*G*C*T*T*A*G*T*+G*+C 17565_17583 C *+C A15229HI CAATTATAACGCACATC +C*+A*+A*T*T*A*T*A*A*C*G*C*A*C*A*+T*+C*+ 17890_17907 C C A15230HI GCCATAATGAGCCATTC +G*+C*+C*A*T*A*A*T*G*A*G*C*C*A*T*T*+C*+ 17972_17990 AC A*+C A15231HI CCATCTACATTAGCTCAT +C*+C*+A*T*C*T*A*C*A*T*T*A*G*C*T*C*+A*+T 18159_18177 C *+C A15232HI CCATCCATCTAGATCTTC +C*+C*+A*T*C*C*A*T*C*T*A*G*A*T*C*+T*+T*+ 18467_18484 C A15233HI TCACCACTTTCAATACCT +T*+C*+A*C*C*A*C*T*T*T*C*A*A*T*A*C*+C*+T 19318_19336 T *+T A15234HI GAGTGAGCTTCAAGAAC +G*+A*+G*T*G*A*G*C*T*T*C*A*A*G*A*A*+C*+ 20338_20356 TA T*+A A15235HI TCAGGACGTATGCCTAC +T*+C*+A*G*G*A*C*G*T*A*T*G*C*C*T*+A*+C* 21156_21173 A +A A15236HI ATCAGGACGTATGCCTA +A*+T*+C*A*G*G*A*C*G*T*A*T*G*C*+C*+T*+A 21158_21174 A15237HI TTGCCAGCTGGAACGGA +T*+T*+G*C*C*A*G*C*T*G*G*A*A*C*G*G*+A*+ 21314_21332 AG A*+G A15238HI CATCTACTACTTTGCCTC +C*+A*+T*C*T*A*C*T*A*C*T*T*T*G*C*C*+T*+C 21657_21675 T *+T A15239HI GTCATCATACATCTACTA +G*+T*+C*A*T*C*A*T*A*C*A*T*C*T*A*+C*+T*+ 21667_21684 A A15240HI CTTAAAGCACACCTCAA +C*+T*+T*A*A*A*G*C*A*C*A*C*C*T*C*A*+A*+ 23307_23325 AC A*+C A15241HI ATGGCATCTGAATAAGC +A*+T*+G*G*C*A*T*C*T*G*A*A*T*A*A*G*+C*+ 23582_23600 TC T*+C A15242HI GACCATAAACCAATTCC +G*+A*+C*C*A*T*A*A*A*C*C*A*A*T*T*C*+C*+ 25301_25319 AA A*+A A15243HI TACCTCTCTCATAACGCC +T*+A*+C*C*T*C*T*C*T*C*A*T*A*A*C*G*+C*+C 26580_26598 T *+T A15244HI GCCTAGTTACTGTATCG +G*+C*+C*T*A*G*T*T*A*C*T*G*T*A*+T*+C*+G 26713_26729 A15245HI AGCCTAGTTACTGTATC +A*+G*+C*C*T*A*G*T*T*A*C*T*G*T*A*+T*+C*+ 26713_26730 G G A15246HI TGTGTTAGGATGTACTG +T*+G*+T*G*T*T*A*G*G*A*T*G*T*A*C*T*+G*+ 26771_26789 CC C*+C A15247HI CCTACCTCCATGAATTAT +C*+C*+T*A*C*C*T*C*C*A*T*G*A*A*T*T*+A*+T 28697_28715 C *+C A15248HI CATAGCTTCCTTGCTTAG +C*+A*+T*A*G*C*T*T*C*C*T*T*G*C*T*T*+A*+G 29197_29215 T *+T A15249HI GATGCATGTTGGAAACC +G*+A*+T*G*C*A*T*G*T*T*G*G*A*A*A*C*+C*+ 30946_30964 TT T*+T A15250HI TAGTACAATAAACTACTC +T*+A*+G*T*A*C*A*A*T*A*A*A*C*T*A*C*+T*+C 31191_31209 C *+C A15251HI ACAGTCCAATCGATTCTT +A*+C*+A*G*T*C*C*A*A*T*C*G*A*T*T*+C*+T*+ 31291_31308 T A15252HI TTACCAATTATGACCTCA +T*+T*+A*C*C*A*A*T*T*A*T*G*A*C*C*T*+C*+A 31753_31771 C *+C A15253HI TGGTAATTAGGTTAGGA +T*+G*+G*T*A*A*T*T*A*G*G*T*T*A*G*G*+A*+ 32077_32095 GT G*+T A15254HI TGTCTCGAAGTCAGAGG +T*+G*+T*C*T*C*G*A*A*G*T*C*A*G*A*G*+G*+ 32606_32624 TT T*+T A15255HI TTCGTATTTAAACTCTAC +T*+T*+C*G*T*A*T*T*T*A*A*A*C*T*C*+T*+A*+ 32729_32746 C A15256HI TAGGTACGAGCATCGGT +T*+A*+G*G*T*A*C*G*A*G*C*A*T*C*+G*+G*+T 32754_32770 A15257HI TAGGTACGAGCATCGG +T*+A*+G*G*T*A*C*G*A*G*C*A*T*+C*+G*+G 32755_32770 A15258HI TTTCTAGTTAATCACACC +T*+T*+T*C*T*A*G*T*T*A*A*T*C*A*C*A*+C*+C 33141_33159 T *+T A15259HI GGTTCCTATGATATGCA +G*+G*+T*T*C*C*T*A*T*G*A*T*A*T*G*C*+A*+ 33945_33963 GT G*+T A15260HI CCAACACCAACCTTCTA +C*+C*+A*A*C*A*C*C*A*A*C*C*T*T*C*T*+A*+ 34015_34033 AC A*+C A15261HI TGAACCATCTGGTAACG +T*+G*+A*A*C*C*A*T*C*T*G*G*T*A*A*C*+G*+ 34754_34772 AC A*+C A15262HI GGTTATTGACTGCTCTCT +G*+G*+T*T*A*T*T*G*A*C*T*G*C*T*C*T*+C*+T 36326_36344 A *+A A15263HI CCAATCCTTAGAACTAC +C*+C*+A*A*T*C*C*T*T*A*G*A*A*C*T*A*+C*+ 36996_37014 CT C*+T A15264HI TTTACACGCATACCACC +T*+T*+T*A*C*A*C*G*C*A*T*A*C*C*A*+C*+C*+ 37454_37471 A A A15265HI GAACTCCGCAAATCTCC +G*+A*+A*C*T*C*C*G*C*A*A*A*T*C*T*C*+C*+ 37700_37718 TC T*+C A15266HI ACTATACTCATCAACTTC +A*+C*+T*A*T*A*C*T*C*A*T*C*A*A*C*+T*+T*+ 38265_38282 C A15267HI CCTACCTTATATCTTACG +C*+C*+T*A*C*C*T*T*A*T*A*T*C*T*T*A*+C*+G 38873_38891 T *+T A15268HI TAATCCTGCTCCTTACAC +T*+A*+A*T*C*C*T*G*C*T*C*C*T*T*A*C*+A*+C 39852_39870 C *+C A15269HI GTAAAGTTGCTTGGACT +G*+T*+A*A*A*G*T*T*G*C*T*T*G*G*A*C*+T*+ 40205_40223 CA C*+A A15270HI ATCAGTCATCACACCAA +A*+T*+C*A*G*T*C*A*T*C*A*C*A*C*C*A*+A*+ 40275_40293 AT A*+T A15271HI CATATCTCAAACGCTTC +C*+A*+T*A*T*C*T*C*A*A*A*C*G*C*+T*+T*+C 42076_42092 A15272HI CACTCATCCATACTCAAC +C*+A*+C*T*C*A*T*C*C*A*T*A*C*T*C*+A*+A*+ 42370_42387 C A15273HI CACGGACCGGAATTACA +C*+A*+C*G*G*A*C*C*G*G*A*A*T*T*+A*+C*+A 42781_42797 A15274HI TACCTCCGATTATTACAT +T*+A*+C*C*T*C*C*G*A*T*T*A*T*T*A*+C*+A*+ 45538_45555 T A15275HI CCACATCAAGTCTCAAT +C*+C*+A*C*A*T*C*A*A*G*T*C*T*C*A*+A*+T*+ 46630_46647 C C A15276HI ATTCACCAACGAACATA +A*+T*+T*C*A*C*C*A*A*C*G*A*A*C*A*+T*+A*+ 49146_49163 C C A15277HI CCAACATACGCCAATCT +C*+C*+A*A*C*A*T*A*C*G*C*C*A*A*T*+C*+T*+ 51438_51455 C C A15278HI CTACCATCTAAAGTGCT +C*+T*+A*C*C*A*T*C*T*A*A*A*G*T*G*C*+T*+ 52304_52322 CC C*+C A15279HI ACCTTTAACTATCTCTAT +A*+C*+C*T*T*T*A*A*C*T*A*T*C*T*C*T*+A*+T 52571_52589 A *+A A15280HI TCTAGGTAGTTTGCTAAT +T*+C*+T*A*G*G*T*A*G*T*T*T*G*C*T*A*+A*+T 53774_53792 C *+C A15281HI CCATCTTTGACACCTCAC +C*+C*+A*T*C*T*T*T*G*A*C*A*C*C*T*C*+A*+C 54734_54752 A *+A A15282HI TTACTCCTTGCCAACTTT +T*+T*+A*C*T*C*C*T*T*G*C*C*A*A*C*T*+T*+T 55748_55766 C *+C A15283HI TTATAACTTGTTCACCTC +T*+T*+A*T*A*A*C*T*T*G*T*T*C*A*C*C*+T*+C 55785_55803 C *+C A15284HI GATGGAATCTTCTAGTG +G*+A*+T*G*G*A*A*T*C*T*T*C*T*A*G*T*+G*+ 55906_55924 TC T*+C A15285HI GCCACACTCTCCTGATT +G*+C*+C*A*C*A*C*T*C*T*C*C*T*G*A*T*+T*+ 56270_56288 GA G*+A A15286HI ATACTGAGATGACCAGT +A*+T*+A*C*T*G*A*G*A*T*G*A*C*C*A*G*+T*+ 57515_57533 TC T*+C A15287HI TAGTCCACCTAACATCTT +T*+A*+G*T*C*C*A*C*C*T*A*A*C*A*T*C*+T*+T 57570_57588 A *+A A15288HI GGCTGCTGGATGTACTT +G*+G*+C*T*G*C*T*G*G*A*T*G*T*A*C*T*+T*+ 57797_57815 AA A*+A A15289HI CCTTCGCCAATCTTATCA +C*+C*+T*T*C*G*C*C*A*A*T*C*T*T*A*T*+C*+A 58000_58018 C *+C A15290HI CCTTCGCCAATCTTATC +C*+C*+T*T*C*G*C*C*A*A*T*C*T*T*+A*+T*+C 58002_58018 A15291HI ACTCCTTCGCCAATCTTA +A*+C*+T*C*C*T*T*C*G*C*C*A*A*T*C*T*+T*+A 58003_58021 T *+T A15292HI CCATAGCATTACTACTTC +C*+C*+A*T*A*G*C*A*T*T*A*C*T*A*C*+T*+T*+ 58197_58214 C A15293HI CTCATCAACTAATACCTC +C*+T*+C*A*T*C*A*A*C*T*A*A*T*A*C*C*+T*+C 59483_59501 A *+A A15294HI CTGGATCAATGAGATGC +C*+T*+G*G*A*T*C*A*A*T*G*A*G*A*T*G*+C*+ 59905_59923 TC T*+C A15295HI CCTCATCCTATCTACGTA +C*+C*+T*C*A*T*C*C*T*A*T*C*T*A*C*+G*+T*+ 61957_61974 A A15296HI ACTCCTCATCCTATCTAC +A*+C*+T*C*C*T*C*A*T*C*C*T*A*T*C*T*+A*+C 61959_61977 G *+G A15297HI AAACACGGCATTGCTCG +A*+A*+A*C*A*C*G*G*C*A*T*T*G*C*+T*+C*+G 62656_62672 A15298HI AGACTAAACGTGTCACC +A*+G*+A*C*T*A*A*A*C*G*T*G*T*C*A*C*+C*+ 62778_62796 AC A*+C A15299HI CCTAGAGACTAAACGTG +C*+C*+T*A*G*A*G*A*C*T*A*A*A*C*G*T*+G*+ 62783_62801 TC T*+C A15300HI TACTGCGCACAAGTTG +T*+A*+C*T*G*C*G*C*A*C*A*A*G*+T*+T*+G 62935_62950 A15301HI TAAATACTAGGCGCTCC +T*+A*+A*A*T*A*C*T*A*G*G*C*G*C*+T*+C*+C 63218_63234 A15302HI TATAGTGCCGGTGGATT +T*+A*+T*A*G*T*G*C*C*G*G*T*G*G*A*+T*+T* 63281_63298 G +G A15303HI GTTGCCTTCCAAGCACA +G*+T*+T*G*C*C*T*T*C*C*A*A*G*C*A*C*+A*+ 63384_63402 AA A*+A A15304HI GATACTTGGCCTGCTAA +G*+A*+T*A*C*T*T*G*G*C*C*T*G*C*T*A*+A*+ 63873_63891 CA C*+A A15305HI GATGCTTCCAGTAGTAG +G*+A*+T*G*C*T*T*C*C*A*G*T*A*G*T*A*+G*+ 63889_63907 AT A*+T A15306HI AAGCCATCACCAATACA +A*+A*+G*C*C*A*T*C*A*C*C*A*A*T*A*+C*+A* 64490_64507 C +C A15307HI CCTCTAAACATATGGCC +C*+C*+T*C*T*A*A*A*C*A*T*A*T*G*G*C*+C*+ 64925_64943 AC A*+C A15308HI GTTCCTTTGTCTATGGTG +G*+T*+T*C*C*T*T*T*G*T*C*T*A*T*G*G*+T*+G 65062_65080 G *+G A15309HI CACGTCCATTGTGTAAG +C*+A*+C*G*T*C*C*A*T*T*G*T*G*T*A*+A*+G* 88422_88439 A +A A15310HI AGCAACAACTCACCACT +A*+G*+C*A*A*C*A*A*C*T*C*A*C*C*A*C*+T*+ 88800_88818 CT C*+T A15311HI AATTTAATCCATCTCTAC +A*+A*+T*T*T*A*A*T*C*C*A*T*C*T*C*T*+A*+C 89990_90008 C *+C A15312HI TTCTCTAGACCATAACTA +T*+T*+C*T*C*T*A*G*A*C*C*A*T*A*A*C*+T*+A 90440_90458 T *+T A15313HI GCTTCTGCAGTGATTGT +G*+C*+T*T*C*T*G*C*A*G*T*G*A*T*T*G*+T*+ 90757_90775 TC T*+C A15314HI GAAATCAACAAACTCCA +G*+A*+A*A*T*C*A*A*C*A*A*A*C*T*C*C*+A*+ 91870_91888 CC C*+C A15315HI CACGCGACATAAATGTA +C*+A*+C*G*C*G*A*C*A*T*A*A*A*T*G*+T*+A* 91953_91970 G +G A15316HI CACGCGACATAAATGTA +C*+A*+C*G*C*G*A*C*A*T*A*A*A*T*+G*+T*+A 91954_91970 A15317HI ATCATCCTCAATCCTAAC +A*+T*+C*A*T*C*C*T*C*A*A*T*C*C*T*A*+A*+C 92535_92553 A *+A A15318HI GTCATCATCCTCAATCCT +G*+T*+C*A*T*C*A*T*C*C*T*C*A*A*T*C*+C*+T 92538_92556 A *+A A15319HI ATTCCAGCCATACTCCAT +A*+T*+T*C*C*A*G*C*C*A*T*A*C*T*C*C*+A*+T 92945_92963 A *+A A15320HI AATTTGCTATGTGCTGC +A*+A*+T*T*T*G*C*T*A*T*G*T*G*C*T*G*+C*+ 92992_93010 CT C*+T A15321HI CTTTAAGGTGTGAACAG +C*+T*+T*T*A*A*G*G*T*G*T*G*A*A*C*A*+G*+ 93258_93276 TC T*+C A15322HI CTCTATTTCAACCACACA +C*+T*+C*T*A*T*T*T*C*A*A*C*C*A*C*A*+C*+A 94681_94699 C *+C A15323HI GATACCTCTATTTCAACC +G*+A*+T*A*C*C*T*C*T*A*T*T*T*C*A*A*+C*+C 94686_94704 A *+A A15324HI ACGGTTGGATACCTCTA +A*+C*+G*G*T*T*G*G*A*T*A*C*C*T*+C*+T*+A 94695_94711 A15325HI TCACACTAACTACATCGT +T*+C*+A*C*A*C*T*A*A*C*T*A*C*A*T*+C*+G*+ 94794_94811 T A15326HI ATCTATCGATACTAATCT +A*+T*+C*T*A*T*C*G*A*T*A*C*T*A*A*T*+C*+T 94892_94910 C *+C A15327HI CACAGCAGATGTTTGGA +C*+A*+C*A*G*C*A*G*A*T*G*T*T*T*G*G*+A*+ 95154_95172 AC A*+C A15328HI AGGTTATAACGAATGCT +A*+G*+G*T*T*A*T*A*A*C*G*A*A*T*G*C*+T*+ 95467_95485 AC A*+C A15329HI TTGACTGCATCACTAGA +T*+T*+G*A*C*T*G*C*A*T*C*A*C*T*A*G*+A*+ 96309_96327 GT G*+T A15330HI CAAATACCTCACTCAAA +C*+A*+A*A*T*A*C*C*T*C*A*C*T*C*A*A*+A*+ 96474_96492 CC C*+C A15331HI ACTACTCTTATCTTAGCA +A*+C*+T*A*C*T*C*T*T*A*T*C*T*T*A*G*+C*+A 96731_96749 T *+T A15332HI ATGCAGTCGCTTTAGAG +A*+T*+G*C*A*G*T*C*G*C*T*T*T*A*G*+A*+G* 102229_102246 T +T A15333HI CCTGTACGTTATCTTAAC +C*+C*+T*G*T*A*C*G*T*T*A*T*C*T*T*+A*+A*+ 109527_109544 C A15334H CATCCTGTCATTTAGCTC +C*+A*+T*C*C*T*G*T*C*A*T*T*T*A*G*C*T*+C* 1657_1676 CG +C*+G A15335H CCTGGATCCGAGAGGAA +C*+C*+T*G*G*A*T*C*C*G*A*G*A*G*G*A*+A*+ 1705_1723 CG C*+G A15336H CGCCTAGAGCTGTACAA +C*+G*+C*C*T*A*G*A*G*C*T*G*T*A*C*A*+A*+ 1763_1781 TC T*+C A15337H CGCCTAGAGCTGTACAA +C*+G*+C*C*T*A*G*A*G*C*T*G*T*A*C*+A*+A* 1764_1781 T +T A15338HI TTGGACGAGAATGCTAT +T*+T*+G*G*A*C*G*A*G*A*A*T*G*C*T*+A*+T* 3187_3204 T +T A15339HI CCGTAAGTCCTTCGTGT +C*+C*+G*T*A*A*G*T*C*C*T*T*C*G*+T*+G*+T 5242_5258 A15340HI GGACTGCTACGTGCAAG +G*+G*+A*C*T*G*C*T*A*C*G*T*G*C*+A*+A*+G 6396_6412 A15341HI GGTTGTTGAGCGCTTTC +G*+G*+T*T*G*T*T*G*A*G*C*G*C*T*T*T*+C*+ 7770_7788 TA T*+A A15342H TCGAAGACTTCCACGTA +T*+C*+G*A*A*G*A*C*T*T*C*C*A*C*G*+T*+A* 65413_65430 G +G A15343H TCGTAGTCAGAGACAAA +T*+C*+G*T*A*G*T*C*A*G*A*G*A*C*A*A*+A*+ 65523_65541 TT T*+T A15344HI CTCTTTAGGCGATTGGA +C*+T*+C*T*T*T*A*G*G*C*G*A*T*T*+G*+G*+A 68528_68544 A15345HI TCATGCTATGGAAGTGA +T*+C*+A*T*G*C*T*A*T*G*G*A*A*G*T*G*+A*+ 70004_70022 TC T*+C A15346HI CAGTATAGTACGCCATT +C*+A*+G*T*A*T*A*G*T*A*C*G*C*C*+A*+T*+T 71685_71701 A15347HI ACAGTATAGTACGCCAT +A*+C*+A*G*T*A*T*A*G*T*A*C*G*C*+C*+A*+T 71686_71702 A15348HI TTACAGGCCATGATGCC +T*+T*+A*C*A*G*G*C*C*A*T*G*A*T*G*+C*+C* 71755_71772 G +G A15349HI GGTAATTCGTACATGT +G*+G*+T*A*A*T*T*C*G*T*A*C*A*+T*+G*+T 71860_71875 A15350H AGGTGTTGTGTAGTTCT +A*+G*+G*T*G*T*T*G*T*G*T*A*G*T*T*C*+T*+ 72403_72421 GG G*+G A15351H CTAGGTGTTGTGTAGTT +C*+T*+A*G*G*T*G*T*T*G*T*G*T*A*G*+T*+T*+ 72406_72423 C C A15352H TATCACTCCACTAGGTG +T*+A*+T*C*A*C*T*C*C*A*C*T*A*G*G*T*+G*+ 72415_72433 TT T*+T A15353HI GATTCACAACACGCATG +G*+A*+T*T*C*A*C*A*A*C*A*C*G*C*+A*+T*+G 75534_75550 A15354HI CGTCTCGTGTGTGTGCT +C*+G*+T*C*T*C*G*T*G*T*G*T*G*T*G*C*+T*+ 76797_76815 CA C*+A A15355HI TTATCCGTCTCGTGTGT +T*+T*+A*T*C*C*G*T*C*T*C*G*T*G*+T*+G*+T 76804_76820 A15356HI AATATTGATCTGAGCGA +A*+A*+T*A*T*T*G*A*T*C*T*G*A*G*C*+G*+A* 76837_76854 G +G A15357HI AGACCTTAGCCTAGCAA +A*+G*+A*C*C*T*T*A*G*C*C*T*A*G*C*A*+A*+ 76861_76879 GC G*+C A15358HI AGCGAGACCTTAGCCTA +A*+G*+C*G*A*G*A*C*C*T*T*A*G*C*+C*+T*+A 76867_76883 A15359HI ACAACAGCGAGACCTTA +A*+C*+A*A*C*A*G*C*G*A*G*A*C*C*T*+T*+A* 76871_76888 G +G A15360HI CGGACAACAGCGTGCCA +C*+G*+G*A*C*A*A*C*A*G*C*G*T*G*C*C*+A*+ 76965_76983 CT C*+T A15361HI TGATCGCCACAGCCGC +T*+G*+A*T*C*G*C*C*A*C*A*G*C*+C*+G*+C 77234_77249 A15362HI ACGAAGTTGTCCATAAC +A*+C*+G*A*A*G*T*T*G*T*C*C*A*T*A*+A*+C* 77470_77487 A +A A15363HI CACGGACAATAGCTTTG +C*+A*+C*G*G*A*C*A*A*T*A*G*C*T*T*T*+G*+ 77702_77720 CA C*+A A15364HI CACGGACAATAGCTTTG +C*+A*+C*G*G*A*C*A*A*T*A*G*C*T*T*+T*+G* 77703_77720 C +C A15365HI GGTTCTGTGCGTTTCAA +G*+G*+T*T*C*T*G*T*G*C*G*T*T*T*C*+A*+A*+ 78318_78335 C C A15366HI TGAGGAGGCGAATGATT +T*+G*+A*G*G*A*G*G*C*G*A*A*T*G*A*T*+T*+ 78948_78966 GG G*+G A15367HI GACTTGAGGAGGCGAAT +G*+A*+C*T*T*G*A*G*G*A*G*G*C*G*A*+A*+T* 78953_78970 G +G A15368HI TGAAGTGGCACCTTGGT +T*+G*+A*A*G*T*G*G*C*A*C*C*T*T*G*G*+T*+ 79475_79493 AC A*+C A15369H TTCTGTCCACAGTAACG +T*+T*+C*T*G*T*C*C*A*C*A*G*T*A*A*+C*+G*+ 79808_79825 C C A15370H GGATTCGACCTGGTGTT +G*+G*+A*T*T*C*G*A*C*C*T*G*G*T*G*T*+T*+ 79824_79842 TT T*+T A15371H GCTGTCGGTGTAAAAAA +G*+C*+T*G*T*C*G*G*T*G*T*A*A*A*A*A*+A*+ 79868_79886 CC C*+C A15372HI GATGCTCAGCCTTGTAT +G*+A*+T*G*C*T*C*A*G*C*C*T*T*G*T*A*+T*+ 80256_80274 GC G*+C A15373HI GCTCTGTCGGTGAACTA +G*+C*+T*C*T*G*T*C*G*G*T*G*A*A*C*+T*+A* 80320_80337 C +C A15374H CCACTCTCGGTAGGAAT +C*+C*+A*C*T*C*T*C*G*G*T*A*G*G*A*+A*+T* 82212_82229 C +C A15375HI TCTCGGAAGAGTAGTAT +T*+C*+T*C*G*G*A*A*G*A*G*T*A*G*+T*+A*+T 82501_82517 A15376HI CATTCTCGGAAGAGTAG +C*+A*+T*T*C*T*C*G*G*A*A*G*A*G*T*+A*+G* 82503_82520 T +T A15377HI ACGTCTATAAACAGGAT +A*+C*+G*T*C*T*A*T*A*A*A*C*A*G*G*A*+T*+ 82637_82655 TC T*+C A15378HI GGTTAGCGTGAGTTCAG +G*+G*+T*T*A*G*C*G*T*G*A*G*T*T*+C*+A*+G 83407_83423 A15379HI TGTTGGAGGTTAGCGTG +T*+G*+T*T*G*G*A*G*G*T*T*A*G*C*G*+T*+G* 83413_83430 A +A A15380HI GGTAGACGTCTCATCTT +G*+G*+T*A*G*A*C*G*T*C*T*C*A*T*C*+T*+T*+ 83455_83472 T T A15381HI GTTCATATCGACAGTTA +G*+T*+T*C*A*T*A*T*C*G*A*C*A*G*T*T*+A*+ 86374_86392 AT A*+T A15382HI GGAAGCTCCAATGTGGA +G*+G*+A*A*G*C*T*C*C*A*A*T*G*T*G*G*+A*+ 86392_86410 CG C*+G A15383HI TCAATGGCTACGTTCAG +T*+C*+A*A*T*G*G*C*T*A*C*G*T*T*C*+A*+G* 86976_86993 G +G A15384HI TTTGCGTGTCAATGGCT +T*+T*+T*G*C*G*T*G*T*C*A*A*T*G*G*C*+T*+ 86983_87001 AC A*+C A15385HI TTTGCGTGTCAATGGCT +T*+T*+T*G*C*G*T*G*T*C*A*A*T*G*G*+C*+T*+ 86984_87001 A A A15386HI GGTGCCTCATTAGAGTT +G*+G*+T*G*C*C*T*C*A*T*T*A*G*A*G*+T*+T* 111327_111344 A +A A15387HI TGGTCGAAAGCTGCACT +T*+G*+G*T*C*G*A*A*A*G*C*T*G*C*A*+C*+T* 112231_112248 C +C A15388HI TGCGTGACTTTAATCCTT +T*+G*+C*G*T*G*A*C*T*T*T*A*A*T*C*C*+T*+T 113865_113883 T *+T A15389HI TACTGTAGACGTGTCAT +T*+A*+C*T*G*T*A*G*A*C*G*T*G*T*C*+A*+T*+ 114058_114075 G G A15390HI TACTGTAGACGTGTCA +T*+A*+C*T*G*T*A*G*A*C*G*T*G*+T*+C*+A 114060_114075 A15391HI CTGTCCTAATCATCGAT +C*+T*+G*T*C*C*T*A*A*T*C*A*T*C*+G*+A*+T 114196_114212 A15392H GACAAATCGAGTTATCA +G*+A*+C*A*A*A*T*C*G*A*G*T*T*A*T*C*+A*+ 114456_114474 GT G*+T A15393H TCGGACAAATCGAGTTA +T*+C*+G*G*A*C*A*A*A*T*C*G*A*G*T*T*+A*+ 114459_114477 TC T*+C A15394H GCAGGCTTGATTCGGAC +G*+C*+A*G*G*C*T*T*G*A*T*T*C*G*G*+A*+C* 114471_114488 A +A A15395H GTTGCAGGCTTGATTCG +G*+T*+T*G*C*A*G*G*C*T*T*G*A*T*+T*+C*+G 114475_114491 A15396HI AGTAGTAGTCAGTATCC +A*+G*+T*A*G*T*A*G*T*C*A*G*T*A*T*C*+C*+ 114958_114976 AG A*+G A15397HI ACGGTGTTCATACCTGC +A*+C*+G*G*T*G*T*T*C*A*T*A*C*C*+T*+G*+C 119145_119161 A15398HI GTAGCCTATCACTAGAT +G*+T*+A*G*C*C*T*A*T*C*A*C*T*A*G*+A*+T*+ 121505_121522 C C A15399HI GTTGCAGACGCATGAAT +G*+T*+T*G*C*A*G*A*C*G*C*A*T*G*A*A*+T*+ 125066_125084 TA T*+A A15400HI GTTGCAGACGCATGAAT +G*+T*+T*G*C*A*G*A*C*G*C*A*T*G*A*+A*+T* 125067_125084 T +T A15401HI GCTTGTTCGGTGGTGGA +G*+C*+T*T*G*T*T*C*G*G*T*G*G*T*G*+G*+A* 126249_126266 A +A A15402HI ATATGTGCTTGTTCGGT +A*+T*+A*T*G*T*G*C*T*T*G*T*T*C*G*+G*+T*+ 126255_126272 G G A15403HI ATATGTGCTTGTTCGGT +A*+T*+A*T*G*T*G*C*T*T*G*T*T*C*+G*+G*+T 126256_126272 AATCGCGTGGAGAGAGC +A*+A*+T*C*G*C*G*T*G*G*A*G*A*G*A*+G*+C* A15404H T +T 128597_128614 A15406H TGAATCGCGTGGAGAG +T*+G*+A*A*T*C*G*C*G*T*G*G*A*+G*+A*+G 128601_128616 A15407H CTGATGAATCGCGTGGA +C*+T*+G*A*T*G*A*A*T*C*G*C*G*T*+G*+G*+A 128604_128620 GTAGATCCTGATGAATC +G*+T*+A*G*A*T*C*C*T*G*A*T*G*A*A*+T*+C* A15408H G +G 128610_128627 ACGAACGCATCTGCAGT +A*+C*+G*A*A*C*G*C*A*T*C*T*G*C*A*+G*+T* A15409HI G +G 129996_130013 A15410HI GGATAGTTCTCGTGAT +G*+G*+A*T*A*G*T*T*C*T*C*G*T*+G*+A*+T 132117_132132 A15411HI TCTGCTAACGCTTATGC +T*+C*+T*G*C*T*A*A*C*G*C*T*T*A*+T*+G*+C 133183_133199 GATCTGCTAACGCTTAT +G*+A*+T*C*T*G*C*T*A*A*C*G*C*T*T*+A*+T*+ A15412HI G G 133184_133201 A15413HI TGGATCTGCTAACGCTT +T*+G*+G*A*T*C*T*G*C*T*A*A*C*G*+C*+T*+T 133187_133203 GGTCGTCATCACATTCA +G*+G*+T*C*G*T*C*A*T*C*A*C*A*T*T*C*+A*+ A15414H TC T*+C 133309_133327 GCCTGGTCGTCATCACA +G*+C*+C*T*G*G*T*C*G*T*C*A*T*C*A*C*+A*+ A15415H TT T*+T 133313_133331 GCAGTTGGCCTGGTCGT +G*+C*+A*G*T*T*G*G*C*C*T*G*G*T*C*G*+T*+ A15416H CA C*+A 133320_133338 TACATGGTAACGCCTTC +T*+A*+C*A*T*G*G*T*A*A*C*G*C*C*T*+T*+C*+ A15417HI A A 134276_134293 AAGTTACATGGTAACGC +A*+A*+G*T*T*A*C*A*T*G*G*T*A*A*C*+G*+C* A15418HI C +C 134280_134297 GGCTGGTTGTTCTGATA +G*+G*+C*T*G*G*T*T*G*T*T*C*T*G*A*+T*+A* A15419HI T +T 134964_134981 A15420HI CCAGGCTAACATACTCG +C*+C*+A*G*G*C*T*A*A*C*A*T*A*C*+T*+C*+G 135046_135062 AACTCGCTGCCATACAC +A*+A*+C*T*C*G*C*T*G*C*C*A*T*A*C*A*+C*+ A15421HI AA A*+A 135069_135087 TAACTCGCTGCCATACA +T*+A*+A*C*T*C*G*C*T*G*C*C*A*T*A*+C*+A*+ A15422HI C C 135071_135088 GATGCAGATTATGGTTG +G*+A*+T*G*C*A*G*A*T*T*A*T*G*G*T*T*+G*+ A15423HI GA G*+A 136582_136600 +C*+G*+T*A*T*C*C*T*A*A*C*A*C*C*T*+T*+T*+ A15424HI CGTATCCTAACACCTTTC C 137784_137801 +A*+C*+G*T*A*T*C*C*T*A*A*C*A*C*C*+T*+T*+ A15425HI ACGTATCCTAACACCTTT T 137785_137802 GTAGACAACGTATCCTA +G*+T*+A*G*A*C*A*A*C*G*T*A*T*C*C*T*+A*+ A15426HI AC A*+C 137791_137809 A15427HI AAGTAGACAACGTATCC +A*+A*+G*T*A*G*A*C*A*A*C*G*T*A*+T*+C*+C 137795_137811 TCAAGTAGACAACGTAT +T*+C*+A*A*G*T*A*G*A*C*A*A*C*G*T*+A*+T* A15428HI C +C 137796_137813 A15429HI TGAAAGCGAGGAGCGCA +T*+G*+A*A*A*G*C*G*A*G*G*A*G*C*+G*+C*+A 138671_138687 +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+ A15430HI GTTACTCCGTTCCTTCAG G 138848_138865 AAAGTATGTTACTCCGTT +A*+A*+A*G*T*A*T*G*T*T*A*C*T*C*C*G*+T*+T A15431HI C *+C 138854_138872 ACAAAGTATGTTACTCC +A*+C*+A*A*A*G*T*A*T*G*T*T*A*C*T*+C*+C*+ A15432HI G G 138857_138874 A15433HI GTCCTAGATGTGCTGCG +G*+T*+C*C*T*A*G*A*T*G*T*G*C*T*+G*+C*+G 138880_138896 A15434HI GATATACACCACACGCC +G*+A*+T*A*T*A*C*A*C*C*A*C*A*C*+G*+C*+C 139434_139450 CAGTGTGGATCAAAGTA +C*+A*+G*T*G*T*G*G*A*T*C*A*A*A*G*T*+A*+ A15435HI TC T*+C 140660_140678 GTGTCATCGGAGAGATA +G*+T*+G*T*C*A*T*C*G*G*A*G*A*G*A*T*+A*+ A15436HI TA T*+A 142207_142225 GGTGCTGTTGGACTATG +G*+G*+T*G*C*T*G*T*T*G*G*A*C*T*A*T*+G*+ A15437HI GT G*+T 143012_143030 CTTGAGCTGCACGTGAT +C*+T*+T*G*A*G*C*T*G*C*A*C*G*T*G*A*+T*+ A15438H TG T*+G 143918_143936 CATGCAGCCGAAGTGAA +C*+A*+T*G*C*A*G*C*C*G*A*A*G*T*G*A*+A*+ A15439HI CT C*+T 143992_144010 AGTAACACAGCCTCGGA +A*+G*+T*A*A*C*A*C*A*G*C*C*T*C*G*G*+A*+ A15440HI AT A*+T 144030_144048 GTTAACAAGTAGTTCCT +G*+T*+T*A*A*C*A*A*G*T*A*G*T*T*C*C*+T*+ A15441HI GC G*+C 146365_146383 TAGCTCCTACATAGCTG +T*+A*+G*C*T*C*C*T*A*C*A*T*A*G*C*T*+G*+ A15442HI TA T*+A 147487_147505 GTGTGAATCTGCTGCTC +G*+T*+G*T*G*A*A*T*C*T*G*C*T*G*C*+T*+C* A15443HI G +G 148534_148551 AGACACTTGCTGAACTG +A*+G*+A*C*A*C*T*T*G*C*T*G*A*A*C*T*+G*+ A15444HI CG C*+G 148689_148707 GTTCATTAGAACGTGCC +G*+T*+T*C*A*T*T*A*G*A*A*C*G*T*G*+C*+C* A15445HI A +A 148720_148737 CTGGTAGCGCAGTTTGA +C*+T*+G*G*T*A*G*C*G*C*A*G*T*T*T*+G*+A* A15446H C +C 149924_149941 TCGTACTCCTCTGGCTTC +T*+C*+G*T*A*C*T*C*C*T*C*T*G*G*C*T*T*+C* A15447H TG +T*+G 149939_149958 GATCGTACTCCTCTGGC +G*+A*+T*C*G*T*A*C*T*C*C*T*C*T*G*+G*+C* A15448H T +T 149943_149960 ACTTTCACTGGAGCATC +A*+C*+T*T*T*C*A*C*T*G*G*A*G*C*A*T*+C*+ A15449HI CG C*+G 151920_151938 CCGAATAAGTACTCTGT +C*+C*+G*A*A*T*A*A*G*T*A*C*T*C*T*G*+T*+ A15450H GT G*+T 156161_156179 CTCCGAATAAGTACTCT +C*+T*+C*C*G*A*A*T*A*A*G*T*A*C*T*C*+T*+ A15451H GT G*+T 156163_156181 TCATGCCTCCGAATAAG +T*+C*+A*T*G*C*C*T*C*C*G*A*A*T*A*+A*+G* A15452H T +T 156170_156187 A15453H TCATGCCTCCGAATAAG +T*+C*+A*T*G*C*C*T*C*C*G*A*A*T*+A*+A*+G 156171_156187 ATGAGTCCGATGGTGAA +A*+T*+G*A*G*T*C*C*G*A*T*G*G*T*G*A*+A*+ A15454H CA C*+A 156359_156377 ACGGAATACGCTTGGTG +A*+C*+G*G*A*A*T*A*C*G*C*T*T*G*G*T*+G*+ A15455H CC C*+C 156545_156563 GAGTTCACAAGCACGAG +G*+A*+G*T*T*C*A*C*A*A*G*C*A*C*G*A*+G*+ A15457H GT G*+T 156805_156823 TATGGAGTTCACAAGCA +T*+A*+T*G*G*A*G*T*T*C*A*C*A*A*G*C*+A*+ A15458H CG C*+G 156809_156827 TAGACTAGCCAGTGCCA +T*+A*+G*A*C*T*A*G*C*C*A*G*T*G*C*C*+A*+ A15459H AG A*+G 156905_156923 ATAGACTAGCCAGTGCC +A*+T*+A*G*A*C*T*A*G*C*C*A*G*T*G*C*+C*+ A15460H AA A*+A 156906_156924 GGTCGTTAATGTAACAC +G*+G*+T*C*G*T*T*A*A*T*G*T*A*A*C*+A*+C* A15461H A +A 156961_156978 AAGCCACGTTGCCAAAT +A*+A*+G*C*C*A*C*G*T*T*G*C*C*A*A*A*+T*+ A15462H CT C*+T 157099_157117 TAAGCCACGTTGCCAAA +T*+A*+A*G*C*C*A*C*G*T*T*G*C*C*A*A*+A*+ A15463H TC T*+C 157100_157118 GTAGTAGTCATAGTTTG +G*+T*+A*G*T*A*G*T*C*A*T*A*G*T*T*T*+G*+ A15464H GA G*+A 158707_158725 A15465HI AATATTTAGGTCCAGCG +A*+A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6714 A15466HI AATATTTAGGTCCAGCG +A*+A*T*+A*T*T*T*A*G*G*T*C*C*+A*G*+C*+G 6698_6714 A15467HI AATATTTAGGTCCAGCG +A*A*+T*+A*T*T*T*A*G*G*T*C*C*+A*+G*C*+G 6698_6714 A15468HI AATATTTAGGTCCAGCG +A*+A*T*A*T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6714 A15469HI AATATTTAGGTCCAGCG +A*A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*C*+G 6698_6714 A15470HI AATATTTAGGTCCAGCG +A*+A*T*A*T*T*T*A*G*G*T*C*C*A*+G*C*+G 6698_6714 A15471HI AATATTTAGGTCCAGCG +A*A*+T*A*T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6714 A15472HI AATATTTAGGTCCAGCG +A*+A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*C*+G 6698_6714 A15473HI ATATTTAGGTCCAGCG +A*T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6713 A15476HI TACATGGTAACGCCTT +T*A*+C*A*T*G*G*T*A*A*C*G*C*+C*T*+T 134278_134293 A15478HI ATATTTAGGTCCAGCG +A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6713 A15480HI ATATTTAGGTCCAGCG +A*T*+A*T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6713 5 A15481HI ATATTTAGGTCCAGCG +A*+T*+A*T*T*T*A*G*G*T*C*C*A*+G*C*+G 6698_6713 5 A15482HI ATATTTAGGTCCAGCG +A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*C*+G 6698_6713 5 A15483HI ATATTTAGGTCCAGCG +A*+T*A*T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6713 5 A15484HI ATATTTAGGTCCAGCG +A*+T*+A*+T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6713 5 A15485HI ATATTTAGGTCCAGCG +A*+T*+A*+T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6713 5 A15486HI ATATTTAGGTCCAGCG +A*+T*+A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G 6698_6713 5 A15487HI ATATTTAGGTCCAGCG +A*+T*A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G 6698_6713 365 neg1 CGTTTAGGCTATGTACTT 5 A15477HI ATATTTAGGTCCAGCG +A*+T*+A*T*T*T*A*G*G*T*C*C*A*G*+C*+G 6698_6713 19 A15488HI TACATGGTAACGCCTT +T*+A*+C*A*T*G*G*T*A*A*C*G*C*C*+T*+T 134278_134293 19 A15489HI TACATGGTAACGCCTT +T*+A*C*A*T*G*G*T*A*A*C*G*C*+C*+T*+T 134278_134293 19 A15490HI TACATGGTAACGCCTT +T*A*+C*A*T*G*G*T*A*A*C*G*C*+C*+T*+T 134278_134293 19 A15491HI TACATGGTAACGCCTT +T*+A*+C*A*T*G*G*T*A*A*C*G*C*+C*T*+T 134278_134293 19 A15492HI TACATGGTAACGCCTT +T*+A*+C*+A*T*G*G*T*A*A*C*G*C*+C*+T*+T 134278_134293 19 A15493HI TACATGGTAACGCCTT +T*+A*+C*+A*T*G*G*T*A*A*C*G*C*C*+T*+T 134278_134293 19 A15494HI TACATGGTAACGCCTT +T*+A*+C*A*T*G*G*T*A*A*C*G*+C*+C*+T*+T 134278_134293 19 A15495HI TACATGGTAACGCCTT +T*+A*C*A*T*G*G*T*A*A*C*G*+C*+C*+T*+T 134278_134293 19 A15496HI TACATGGTAACGCCTT +T*+A*+C*+A*T*G*G*T*A*A*C*G*C*+C*T*+T 134278_134293 19 A15497HI TACATGGTAACGCCTT +T*+A*C*+A*T*G*G*T*A*A*C*G*C*+C*+T*+T 134278_134293 19 A15498HI TACATGGTAACGCCTT +T*A*+C*A*T*G*G*T*A*A*C*G*+C*+C*+T*+T 134278_134293 19 A15499HI TACATGGTAACGCCTT +T*+A*+C*A*T*G*G*T*A*A*C*G*+C*C*+T*+T 134278_134293 330 A15500HI GTTACTCCGTTCCTTCAG +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*T*C*+A*+G 138848_138865 330 A15501HI GTTACTCCGTTCCTTCAG +G*+T*T*A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+G 138848_138865 330 A15502HI GTTACTCCGTTCCTTCAG +G*T*+T*A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+G 138848_138865 330 A15503HI GTTACTCCGTTCCTTCAG +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*T*+C*A*+G 138848_138865 330 +G*+T*+T*+A*C*T*C*C*G*T*T*C*C*T*T*+C*+A* A15504HI GTTACTCCGTTCCTTCAG +G 138848_138865 330 +G*+T*+T*+A*C*T*C*C*G*T*T*C*C*T*T*C*+A*+ A15505HI GTTACTCCGTTCCTTCAG G 138848_138865 330 +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*+T*+C*+A* A15506HI GTTACTCCGTTCCTTCAG +G 138848_138865 330 +G*+T*T*A*C*T*C*C*G*T*T*C*C*T*+T*+C*+A*+ A15507HI GTTACTCCGTTCCTTCAG G 138848_138865 330 +G*+T*+T*+A*C*T*C*C*G*T*T*C*C*T*T*+C*A*+ A15508HI GTTACTCCGTTCCTTCAG G 138848_138865 330 +G*+T*T*+A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+ A15509HI GTTACTCCGTTCCTTCAG G 138848_138865 330 +G*T*+T*A*C*T*C*C*G*T*T*C*C*T*+T*+C*+A*+ A15510HI GTTACTCCGTTCCTTCAG G 138848_138865 330 +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*+T*C*+A*+ A15511HI GTTACTCCGTTCCTTCAG G 138848_138865 5 A15479HI ATATTTAGGTCCAGCG +A*T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G 6698_6713 Table 1: List of human NRP1-specific oligonucleotides, in particular ASOs. An “H” after the ASO ID indicates a human NRP1-specific sequence that binds to an exonic region of the pre-mRNA, a “HMI” after the ASO ID indicates a human / mouse cross-reactive NRP1 sequence that binds to an intronic region of the pre-mRNA and a “HI” after the ASO ID indicates a human NRP1-specific sequence that binds to an intronic region of the pre-mRNA. # is exon spanning oligonucleotide; position for these uses RefSeq ID NM_003873.6 (SEQ ID NO.367). **The human NRP1 gene is located on the lagging strand of the DNA (indicated by “-1”), which has been used to determine binding sites of the respective ASOs. The ASOs of the present invention hybridize, for example, with hybridizing active regions of SEQ ID NOs.366 and/or 367. Such regions comprise or consist, for example, of positions 1650-1949, 3150-3449, 4050-4349, 4650-4949, 4950-5249, 5550-5849, 6150- 6449, 6450-6749, 7650-7949, 9450-9749, 9750-10049, 10950-11249, 12150-12449, 12450- 12749, 13350-13649, 14250-14549, 14550-14849, 15450-15749, 15750-16049, 17550- 17849, 17850-18149, 18150-18449, 18450-18749, 19050-19349, 20250-20549, 21150- 21449, 21450-21749, 23250-23549, 23550-23849, 25050-25349, 26550-26849, 28650- 28949, 28950-29249, 30750-31049, 31050-31349, 31650-31949, 31950-32249, 32550- 32849, 32850-33149, 33750-34049, 34650-34949, 36150-36449, 36750-37049, 37350- 37649, 37650-37949, 38250-38549, 38850-39149, 39750-40049, 40050-40349, 41850- 42149, 42150-42449, 42750-43049, 45450-45749, 46350-46649, 49050-49349, 51150- 51449, 52050-52349, 52350-52649, 53550-53849, 54450-54749, 55650-55949, 56250- 56549, 57450-57749, 57750-58049, 58050-58349, 59250-59549, 59850-60149, 61950- 62249, 62550-62849, 62850-63149, 63150-63449, 63750-64049, 64350-64649, 64650- 64949, 64950-65249, 65250-65549, 66150-66449, 67050-67349, 67650-67949, 68250- 68549, 69450-69749, 69750-70049, 70350-70649, 71550-71849, 71850-72149, 72150- 72449, 72450-72749, 73650-73949, 74850-75149, 75450-75749, 76650-76949, 76950- 77249, 77250-77549, 77550-77849, 78150-78449, 78450-78749, 78750-79049, 79350- 79649, 79650-79949, 80250-80549, 80550-80849, 82050-82349, 82350-82649, 83250- 83549, 83850-84149, 85350-85649, 86250-86549, 86850-87149, 88350-88649, 88650- 88949, 89850-90149, 90150-90449, 91650-91949, 91950-92249, 92250-92549, 92850- 93149, 93150-93449, 94650-94949, 94950-95249, 95250-95549, 96150-96449, 96450- 96749, 102150-102449, 109350-109649, 109950-110249, 110550-110849, 111150-111449, 111750-112049, 112050-112349, 113850-114149, 114150-114449, 114450-114749, 114750-115049, 116850-117149, 118950-119249, 120150-120449, 121350-121649, 121650-121949, 122850-123149, 123150-123449, 124950-125249, 126150-126449, 128550-128849, 128850-129149, 129150-129449, 129750-130049, 130050-130349, 131850-132149, 132750-133049, 133050-133349, 133350-133649, 134250-134549, 134550-134849, 134850-135149, 136350-136649, 137550-137849, 138450-138749, 138750-139049, 139050-139349, 139350-139649, 139650-139949, 140550-140849, 142050-142349, 142950-143249, 143850-144149, 144450-144749, 145950-146249, 146250-146549, 147450-147749, 148350-148649, 148650-148949, 149850-150149, 150150-150449, 151650-151949, 152550-152849, 154350-154649, 154950-155249, 155850-156149, 156150-156449, 156450-156749, 156750-157049, 157050-157349, 157950-158249, and/or 158550-158849 of SEQ ID NO.366. Oligonucleotides, in particular antisense oligonucleotides (ASOs) hybridizing in these regions are shown in the following Table 2: on mRNA First position on pre- SEQ ID

mRNA NO. 1650-1949 A15187H 1702 88 A15188H 1790 89 A15189H 1796 90 A15334H 1657 235 A15335H 1705 236 A15336H 1763 237 A15337H 1764 238 3150-3449 A15090HI 3189 4 A15115HI 3189 24 A15338HI 3187 239 4050-4349 A15116HI 4071 25 4650-4949 A15117HI 4717 26 4950-5249 A15339HI 5242 240 5550-5849 A15119HI 5594 27 6150-6449 A15340HI 6396 241 6450-6749 A15091HI 6698 5 A15465HI 6698 364 _{A15466HI 6698} ³⁶⁴ _{A15467HI 6698} ³⁶⁴ _{A15468HI 6698} ³⁶⁴ _{A15469HI 6698} ³⁶⁴ _{A15470HI 6698} ³⁶⁴ _{A15471HI 6698} ³⁶⁴ _{A15472HI 6698} ³⁶⁴ A15473HI 6698 5 A15477HI 6698 5 A15478HI 6698 5 A15480HI 6698 5 A15481HI 6698 5 A15482HI 6698 5 A15483HI 6698 5 A15484HI 6698 5 A15485HI 6698 5 A15486HI 6698 5 A15487HI 6698 5 7650-7949 A15120HI 7798 28 A15341HI 7770 242 9450-9749 A15121HI 9480 29 9750-10049 A15092HI 9942 6 10950-11249 A15217HI 11165 118 12150-12449 A15218HI 12172 119 A15219HI 12282 120 12450-12749 A15220HI 12705 121 13350-13649 A15221HI 13391 122 14250-14549 A15222HI 14399 123 A15223HI 14519 124 14550-14849 A15224HI 14576 125 15450-15749 A15225HI 15563 126 A15226HI 15567 127 15750-16049 A15227HI 15898 128 17550-17849 A15228HI 17565 129 17850-18149 A15229HI 17890 130 A15230HI 17972 131 18150-18449 A15231HI 18159 132 18450-18749 A15232HI 18467 133 19050-19349 A15233HI 19318 134 20250-20549 A15234HI 20338 135 21150-21449 A15235HI 21156 136 A15236HI 21158 137 A15237HI 21314 138 21450-21749 A15238HI 21657 139 A15239HI 21667 140 23250-23549 A15240HI 23307 141 23550-23849 A15241HI 23582 142 25050-25349 A15242HI 25301 143 26550-26849 A15243HI 26580 144 A15244HI 26713 145 A15245HI 26713 146 A15246HI 26771 147 28650-28949 A15247HI 28697 148 28950-29249 A15248HI 29197 149 30750-31049 A15249HI 30946 150 31050-31349 A15250HI 31191 151 A15251HI 31291 152 31650-31949 A15252HI 31753 153 31950-32249 A15253HI 32077 154 32550-32849 A15254HI 32606 155 A15255HI 32729 156 A15256HI 32754 157 A15257HI 32755 158 32850-33149 A15258HI 33141 159 33750-34049 A15259HI 33945 160 A15260HI 34015 161 34650-34949 A15261HI 34754 162 36150-36449 A15262HI 36326 163 36750-37049 A15263HI 36996 164 37350-37649 A15264HI 37454 165 37650-37949 A15265HI 37700 166 38250-38549 A15266HI 38265 167 38850-39149 A15267HI 38873 168 39750-40049 A15268HI 39852 169 40050-40349 A15269HI 40205 170 A15270HI 40275 171 41850-42149 A15271HI 42076 172 42150-42449 A15272HI 42370 173 42750-43049 A15273HI 42781 174 45450-45749 A15274HI 45538 175 46350-46649 A15275HI 46630 176 49050-49349 A15276HI 49146 177 51150-51449 A15277HI 51438 178 52050-52349 A15278HI 52304 179 52350-52649 A15279HI 52571 180 53550-53849 A15280HI 53774 181 54450-54749 A15281HI 54734 182 55650-55949 A15282HI 55748 183 A15283HI 55785 184 A15284HI 55906 185 56250-56549 A15285HI 56270 186 57450-57749 A15286HI 57515 187 A15287HI 57570 188 57750-58049 A15288HI 57797 189 A15289HI 58000 190 A15290HI 58002 191 A15291HI 58003 192 58050-58349 A15292HI 58197 193 59250-59549 A15293HI 59483 194 59850-60149 A15294HI 59905 195 61950-62249 A15295HI 61957 196 A15296HI 61959 197 62550-62849 A15297HI 62656 198 A15298HI 62778 199 A15299HI 62783 200 62850-63149 A15300HI 62935 201 63150-63449 A15301HI 63218 202 A15302HI 63281 203 A15303HI 63384 204 63750-64049 A15304HI 63873 205 A15305HI 63889 206 64350-64649 A15306HI 64490 207 64650-64949 A15307HI 64925 208 64950-65249 A15308HI 65062 209 65250-65549 A15191H 65534 192 A15342H 65413 243 A15343H 65523 244 66150-66449 A15122HI 66440 30 67050-67349 A15093HI 67280 7 A15123HI 67174 31 67650-67949 A15124HI 67717 32 68250-68549 A15125HI 68291 33 A15344HI 68528 245 69450-69749 A15126HI 69620 34 69750-70049 A15345HI 70004 246 70350-70649 A15095HI 70457 8 A15127HI 70356 35 A15128HI 70456 36 A15129HI 70457 37 A15130HI 70639 38 71550-71849 A15131HI 71688 39 A15346HI 71685 247 A15347HI 71686 248 A15348HI 71755 249 71850-72149 A15132HMI 71865 40 A15349HI 71860 250 72150-72449 A15350H 72403 251 A15351H 72406 252 A15352H 72415 253 72450-72749 A15192H 72581 93 73650-73949 A15096HI 73841 9 74850-75149 A15134HI 75045 41 75450-75749 A15097HI 75724 10 A15353HI 75534 254 76650-76949 A15136HI 76807 42 A15137HI 76865 43 A15354HI 76797 255 A15355HI 76804 256 A15356HI 76837 257 A15357HI 76861 258 A15358HI 76867 259 A15359HI 76871 260 76950-77249 A15360HI 76965 261 A15361HI 77234 262 77250-77549 A15362HI 77470 263 77550-77849 A15363HI 77702 264 A15364HI 77703 265 78150-78449 A15138HI 78359 44 A15365HI 78318 266 78450-78749 A15139HI 78469 45 78750-79049 A15366HI 78948 267 A15367HI 78953 268 79350-79649 A15368HI 79475 269 79650-79949 A15193H 79878 94 A15194H 79883 95 A15369H 79808 270 A15370H 79824 271 A15371H 79868 272 80250-80549 A15098HI 80321 11 A15372HI 80256 273 A15373HI 80320 274 80550-80849 A15140HI 80608 46 82050-82349 A15141HI 82336 47 A15374H 82212 275 82350-82649 A15087HI 82429 1 A15375HI 82501 276 A15376HI 82503 277 A15377HI 82637 278 83250-83549 A15142HI 83459 56 A15378HI 83407 279 A15379HI 83413 280 A15380HI 83455 281 83850-84149 A15088HI 84119 2 A15143HI 84073 49 85350-85649 A15099HI 85422 12 86250-86549 A15381HI 86374 282 A15382HI 86392 283 86850-87149 A15144HI 86990 50 A15383HI 86976 284 A15384HI 86983 285 A15385HI 86984 286 88350-88649 A15309HI 88422 210 88650-88949 A15310HI 88800 211 89850-90149 A15311HI 89990 212 90150-90449 A15312HI 90440 213 90750-91049 A15313HI 90757 214 91650-91949 A15314HI 91870 215 91950-92249 A15315HI 91953 216 A15316HI 91954 217 92250-92549 A15317HI 92535 218 A15318HI 92538 219 92850-93149 A15319HI 92945 220 A15320HI 92992 221 93150-93449 A15321HI 93258 222 94650-94949 A15322HI 94681 223 A15323HI 94686 224 A15324HI 94695 225 A15325HI 94794 226 A15326HI 94892 227 94950-95249 A15327HI 95154 228 95250-95549 A15328HI 95467 229 96150-96449 A15329HI 96309 230 96450-96749 A15330HI 96474 231 A15331HI 96731 232 102150-102449 A15332HI 102229 233 109350-109649 A15333HI 109527 234 109950-110249 A15195H 109995 96 A15196H 110064 97 A15197H 110069 98 110550-110849 A15100HI 110590 13 111150-111449 A15386HI 111327 287 111750-112049 A15145HI 112045 51 112050-112349 A15387HI 112231 288 113850-114149 A15146HI 113961 52 A15388HI 113865 289 A15389HI 114058 290 A15390HI 114060 291 114150-114449 A15089HI 114263 3 A15147HI 114198 53 A15391HI 114196 292 114450-114749 A15198H 114474 99 A15199H 114518 100 A15200H 114522 101 A15392H 114456 293 A15393H 114459 294 A15394H 114471 295 A15395H 114475 296 114750-115049 A15396HI 114958 297 116850-117149 A15148HI 116868 54 A15149HI 116869 55 A15150HI 116870 56 118950-119249 A15152HI 119021 57 A15397HI 119145 298 120150-120449 A15102HI 120213 14 A15153HI 120437 58 121350-121649 A15154HI 121509 59 A15398HI 121505 299 121650-121949 A15155HI 121719 60 122850-123149 A15201H 122860 102 123150-123449 A15157HI 123201 61 124950-125249 A15158HI 125068 62 A15399HI 125066 300 A15400HI 125067 301 126150-126449 A15159HI 126252 63 A15401HI 126249 302 A15402HI 126255 303 A15403HI 126256 304 128550-128849 A15202H 128600 103 A15203H 128606 104 A15404H 128597 305 A15406H 128601 306 A15407H 128604 307 A15408H 128610 308 128850-129149 A15160HI 128901 64 129150-129449 A15103HI 129192 15 A15162HI 129187 65 129750-130049 A15104HI 130003 16 A15163HI 130003 66 A15409HI 129996 309 130050-130349 A15164HI 130092 67 131850-132149 A15165HI 131977 68 A15410HI 132117 310 132750-133049 A15105HI 133045 17 A15106HI 133046 18 A15166HI 133045 69 133050-133349 A15411HI 133183 311 A15412HI 133184 312 A15413HI 133187 313 A15414H 133309 314 A15415H 133313 315 A15416H 133320 316 133350-133649 A15167HI 133452 70 134250-134549 A15108HI 134278 19 A15417HI 134276 317 A15418HI 134280 318 A15476HI 134278 19 A15488HI 134278 19 A15489HI 134278 19 A15490HI 134278 19 A15491HI 134278 19 A15492HI 134278 19 A15493HI 134278 19 A15494HI 134278 19 A15495HI 134278 19 A15496HI 134278 19 A15497HI 134278 19 A15498HI 134278 19 A15499HI 134278 19 134550-134849 A15168HI 134718 71 134850-135149 A15169HI 135077 72 A15419HI 134964 319 A15420HI 135046 320 A15421HI 135069 321 A15422HI 135071 322 136350-136649 A15423HI 136582 323 137550-137849 A15109HI 137700 20 A15170HI 137701 73 A15424HI 137784 324 A15425HI 137785 325 A15426HI 137791 326 A15427HI 137795 327 A15428HI 137796 328 138450-138749 A15429HI 138671 329 138750-139049 A15430HI 138848 330 A15431HI 138854 331 A15432HI 138857 332 A15433HI 138880 333 A15500HI 138848 330 A15501HI 138848 330 A15502HI 138848 330 A15503HI 138848 330 A15504HI 138848 330 A15505HI 138848 330 A15506HI 138848 330 A15507HI 138848 330 A15508HI 138848 330 A15509HI 138848 330 A15510HI 138848 330 A15511HI 138848 330 139050-139349 A15110HI 139201 21 A15171HI 139177 74 A15172HI 139207 75 139350-139649 A15434HI 139434 334 139650-139949 A15111HI 139705 22 A15173HI 139705 76 140550-140849 A15435HI 140660 335 142050-142349 A15174HI 142075 77 A15436HI 142207 336 142950-143249 A15175HI 143247 78 A15437HI 143012 337 143850-144149 A15176HI 143993 79 A15438H 143918 338 A15439HI 143992 339 A15440HI 144030 340 144450-144749 A15177HI 144645 80 145950-146249 A15113HI 146184 23 146250-146549 A15178HI 146368 81 A15441HI 146365 341 147450-147749 A15442HI 147487 342 148350-148649 A15443HI 148534 343 148650-148949 A15444HI 148689 344 A15445HI 148720 345 149850-150149 A15204H 149906 105 A15205H 149926 106 A15206H 149943 107 A15446H 149924 346 A15447H 149939 347 A15448H 149943 348 150150-150449 A15181HI 150411 82 151650-151949 A15182HI 151847 83 A15449HI 151920 349 152550-152849 A15183HI 152763 84 A15184HI 152817 85 154350-154649 A15185HI 154440 86 154950-155249 A15186HMI 155098 87 155850-156149 A15207H 155903 108 156150-156449 A15208H 156169 109 A15209H 156321 110 A15210H 156364 111 A15450H 156161 350 A15451H 156163 351 A15452H 156170 352 A15453H 156171 353 A15454H 156359 354 156450-156749 A15211H 156551 112 A15212H 156671 113 A15455H 156545 355 156750-157049 A15213H 156754 114 A15214H 156795 115 A15457H 156805 356 A15458H 156809 357 A15459H 156905 358 A15460H 156906 359 A15461H 156961 360 157050-157349 A15462H 157099 361 A15463H 157100 362 157950-158249 A15215H 158027 116 A15216H 158075 117 158550-158849 A15464H 158707 363 Table 2 shows some hybridizing active regions and oligonucleotides, in particular antisense oligonucleotides hybridizing in these regions. ** The human NRP1 gene is located on the lagging strand of the DNA (indicated by “-1”), which has been used to determine hybridizing active regions. The oligonucleotides of the present invention hybridize, for example, with pre-mRNA and/or mRNA of human NRP1 of SEQ ID NO.366 and/or SEQ ID NO.367. Such oligonucleotides are called NRP1 antisense oligonucleotides. Oligonucleotides of the present invention, which are for example antisense oligonucleotides, are shown in Table 1. The present invention further refers to oligonucleotides such as antisense oligonucleotides having about 80 % to 99 %, about 85 % to 98 %, about 90 % to 95 %, about 90 % to 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, at least about 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, or 99 % sequence homology to an oligonucleotide of Table 1. Moreover, the present invention refers to oligonucleotides such as antisense oligonucleotides comprising or consisting of at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 nucleotides of any one of the oligonucleotides of SEQ ID NO.1 – SEQ ID NO.364. Each nucleotide of the sequence can be modified, wherein ASOs of the present invention preferably comprise a core of 6 to 8 unmodified nucleotides. ASOs of the present invention comprise, for example, one or more modified nucleotides, e.g., 1, 2, 3, 4 or 5 nucleotides at the 5´- and/or 3´-end of the oligonucleotide, i.e., on the 5´- and/or 3´-side of the core. The 5´- and 3´-end are modified identically or differently. If the 5´- and 3´-ends are modified identically the nucleotides are modified at the same positions counted from the 5´- and 3´-end (in each case starting the counting with 1 from the end), respectively, having the same modification for example LNA-modification. If the 5´- and 3´-ends are modified differently the position of the modified nucleotide and/or the type of modification at the 5´- and 3´-ends differ; the type of nucleotide modification is the same (e.g., LNA) or different. Modified nucleotides such as LNA-modified nucleotides need not to follow in a row, but may be separated by one or more unmodified nucleotides. In the following table exemplary modification patterns at the 5´- and 3´-end of the ASOs of the present invention are described, wherein an unmodified nucleotide is indicated by “_” and the number on either side of the “_” refers to the number of modified nucleotides such as LNA-modified nucleotides in a row. The modified nucleotide(s) is/are at any position of the 5´- and/or 3´-end of the ASO as shown for example in the following Table 3: LNA modification at the LNA modification at the Abbreviation 5´-side of the core 3´-side of the core 3 3 3+3 3 2 3+2 2 3 2+3 1_1 3 1_1+3 1_1 2 1_1+2 1_1 1_1 1_1+1_1 3 1_1 3+1_1 2 1_1 2+1_1 2 2 2+2 4 3 4+3 4 2 4+2 4 1_1 4+1_1 2_1 3 2_1+3 2_1 1_1 2_1+1_1 2_1 2 2_1+2 3 4 3+4 2 4 2+4 1_1 4 1_1+4 3 1_2 3+1_2 1_1 1_2 1_1+1_2 2 1_2 2+1_2 which indicates specific positions of the LNA modifications at the 5´- and 3´-end of each ASO in the following Table 4: Position of the Position of the Abbreviation modification at the 5´-end modification at the 3´-end (counted from the 5´-end (counted from the 3´-end starting with 1) starting with 1) nucleotides 1 to 5 nucleotides 1 to 5 5+5 nucleotides 1 to 4 nucleotides 1 to 4 4+4 nucleotides 1 to 3 nucleotides 1 to 3 3+3 nucleotides 1 and 2 nucleotides 1 and 2 2+2 nucleotide 1 nucleotide 1 1+1 nucleotides 1 to 5 nucleotides 1 to 4 5+4 nucleotides 1 to 4 nucleotides 1 to 3 4+3 nucleotides 1 to 3 nucleotides 1 and 2 3+2 nucleotides 1 and 2 nucleotide 1 2+1 nucleotide 1 nucleotides 1 to 5 1+5 nucleotides 1 to 5 nucleotides 1 to 3 5+3 nucleotides 1 to 4 nucleotides 1 and 2 4+2 nucleotides 1 to 3 nucleotide 1 3+1 nucleotides 1 and 2 nucleotides 1 to 5 2+5 nucleotide 1 nucleotides 1 to 4 1+4 nucleotides 1 to 5 nucleotides 1 and 2 5+2 nucleotides 1 to 4 nucleotide 1 4+1 nucleotides 1 to 3 nucleotides 1 to 5 3+5 nucleotides 1 and 2 nucleotides 1 to 4 2+4 nucleotide 1 nucleotides 1 to 3 1+3 nucleotides 1 to 5 nucleotide 1 5+1 nucleotides 1 to 4 nucleotides 1 to 5 4+5 nucleotides 1 to 3 nucleotides 1 to 4 3+4 nucleotides 1 and 2 nucleotides 1 to 3 2+3 nucleotide 1 nucleotides 1 and 2 1+2 nucleotides 1 and 2 nucleotides 1 and 3 2+1_1 nucleotides 1 and 3 nucleotides 1 to 3 1_1+3 nucleotides 1 and 3 nucleotides 1 and 3 1_1+1_1 nucleotides 1 to 3 nucleotides 1 and 3 3+1_1 nucleotides 1 to 4 nucleotides 1 and 3 4+1_1 nucleotides 1, 2 and 4 nucleotides 1 to 3 2_1+3 nucleotides 1, 2 and 4 nucleotides 1 and 3 2_1+1_1 nucleotides 1, 2 and 4 nucleotides 1 and 2 2_1+2 nucleotides 1 and 3 nucleotides 1 to 4 1_1+4 nucleotides 1 to 3 nucleotides 1,2 and 4 3+1_2 nucleotides 1 and 3 nucleotides 1, 2 and 4 1_1+1_2 nucleotides 1 and 2 nucleotides 1, 2 and 4 2+1_2 In some embodiments, an oligonucleotide of the present invention reduces the amount of NRP1 mRNA and/or the NRP1 protein expression for example by about 30 % - 100 %, 35 % - 99 %, 40 % - 98 %, 45 % - 97 %, 50 % - 96 %, 55 % - 95 %, 60 % - 90 %, 65 % - 85 %, 70 % - 80 % or at least about 30 %, 35 %, 40 %, 45 %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. The NRP1 mRNA and/or protein expression is for example reduced in a cell, tissue, organ, or a subject. The reduction of the amount of the NRP1 mRNA and/or NRP1 protein expression is for example determined by the comparison of the amount of the NRP1 mRNA and/or NRP1 protein expression in a sample treated with an oligonucleotide of the present invention and a corresponding untreated control. The untreated control is, for example, NRP1, NRP1 mRNA, NRP1 pre-mRNA expression, or a combination thereof in a subject prior to administration of an oligonucleotide of the present invention is administered or an untreated sample such as a cell, blood, urine, saliva etc.. The untreated sample is, for example, taken from a subject before an oligonucleotide of the present invention is administered. The oligonucleotide of the present invention reduces the amount of NRP1 mRNA and/or the expression of NRP1 protein expression at a nanomolar or micromolar concentration for example at a concentration of about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 or 950 nM, or 1, 10 or 100 µM. The oligonucleotide of the present invention is for example used in a concentration of about 1, 3, 5, 9, 10, 15, 27, 30, 40, 50, 75, 82, 100, 250, 300, 500, or 740 nM, or 1, 2.2, 3, 5, 6.6 or 10 μM. The present invention also refers to a pharmaceutical composition comprising an oligonucleotide of the present invention and a pharmaceutically acceptable carrier, excipient and/or diluent. Optionally the pharmaceutical composition further comprises for example a chemotherapeutic, another oligonucleotide either from the present invention or different from the present invention, an antagonistic protein such as a fusion protein, an antibody and/or a small molecule. In some embodiments, the oligonucleotide or the pharmaceutical composition of the present invention is for use in a method of preventing and/or treating a disorder. In some embodiments, the use of the oligonucleotide or the pharmaceutical composition of the present invention in a method of preventing and/or treating a disorder is combined with radiotherapy and/or laser treatment. The radiotherapy may be further combined with a chemotherapy (e.g., platinum, gemcitabine). The disorder is, for example, characterized by activity of NRP1, such as overactivity or a NRP1 mRNA and/or protein imbalance, i.e., the NRP1 mRNA and/or protein level is abnormal (e.g., increased) in comparison to the level in a normal, healthy cell, tissue, organ or subject, or NRP1 activity is abnormal. The NRP1 level is, for example, increased by an increased amount of NRP1 mRNA and/or NRP1 protein expression. Overactivity of NRP1 function is, for example, caused by activating mutations or by unknown genetic, epigenetic or environmental mechanisms. The NRP1 mRNA and protein level, respectively, is measured for example by any standard method known to a person skilled in the art, such as immunohistochemistry, western blot, quantitative real time PCR or QuantiGene assay. The oligonucleotide and the pharmaceutical composition comprising the oligonucleotide, respectively, of the present invention has an inhibitory effect on the NRP1 expression for example for 1, 2, 3, 4, 5 or 6 days, 1, 2 or 3 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months or 1 or 2 years. The treatment effect of the oligonucleotides of the present invention for example corresponds to the duration of the inhibitory effect. An oligonucleotide or a pharmaceutical composition of the present invention is administered locally or systemically for example intravitreal, intracameral or subconjunctival, e.g., injection, topically via eye drops, orally, sublingually, nasally, subcutaneously, intravenously, intraperitoneally, intramuscularly, intratumorally, intrathecally, intraventricularily, transdermally, and/or rectally. Alternatively or in combination ex vivo treated immune cells are administered. The oligonucleotide is administered alone or in combination with another oligonucleotide of the present invention and optionally in combination with another compound such as another oligonucleotide, an antagonistic protein such as a fusion protein, an antibody, a small molecule and/or a chemotherapeutic (e.g., platinum, gemcitabine). Further, two or more oligonucleotides of the present invention are, for example, administered together, at the same time point, e.g., in a pharmaceutical composition or separately, or on staggered intervals. In some embodiments, the other oligonucleotide (i.e., not being part of the present invention), the antagonistic protein such as a fusion protein, the antibody, and/or the small molecule are effective in preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder. An autoimmune disorder is for example autoimmune arthritis or gastrointestinal autoimmune diseases such as inflammatory bowel disease (IBD) or colitis, an immune disorder for example an immune exhaustion due to chronic viral infections such as HIV infection, a cardiovascular disorder, an inflammatory disorder for example a chronic airway inflammation, a bacterial, viral and/or fungal infection for example sepsis, a corona virus infection or a Mycobacterium bovis infection, a liver disorder, a chronic kidney disorder, a psychiatric disorder (e.g., schizophrenia, bipolar disorders, Alzheimer´s disease), cancer or a combination thereof. An oligonucleotide or a pharmaceutical composition of the present invention is used for example in a method of preventing and/or treating a solid tumor or a hematologic tumor. Examples of cancers preventable and/or treatable by use of the oligonucleotide or pharmaceutical composition of the present invention are bladder carcinoma, breast cancer, colorectal carcinoma, lung cancer, malignant melanoma, mesothelioma, lymphoma, skin cancer, bone cancer, prostate cancer, hepatocarcinoma, brain cancer, cancer of the larynx, liver, gall bladder, pancreas, testicular, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, neuroblastoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, liposarcoma, leukemia, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, meningioma, acute and chronic lymphocytic and granulocytic tumors, acute and chronic myeloid leukemia, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, intestinal ganglioneuromas, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, polycythaemia vera, adenocarcinoma, anaplastic astrocytoma, glioblastoma multiforma, leukemia, or epidermoid carcinoma. In some embodiments two or more oligonucleotides of the present invention are administered together, at the same time point for example in a pharmaceutical composition or separately, or on staggered intervals. In other embodiments, one or more oligonucleotides of the present invention are administered together with another compound such as another oligonucleotide (i.e., not being part of the present invention), an antagonistic protein such as a fusion protein, an antibody, a small molecule and/or a chemotherapeutic, at the same time point for example in a pharmaceutical composition or separately, or on staggered intervals. In some embodiments of these combinations, the oligonucleotide inhibits the expression and activity, respectively, of an receptor such as an growth receptor and the other oligonucleotide (i.e., not being part of the present invention), an antagonistic protein such as a fusion protein, the antibody and/or small molecule inhibits (antagonist) the identical or a different growth receptor or it inhibits (antagonist) a signal transduction factor. The growth receptor is for example TGF-beta receptor I (TβRI), TGF-beta receptor II (TβRII), or receptors for VEGF, HGF, PDGF and/ or SEMA3 (Plexin). The signal transduction factor is for example p38MAPK, ERK1, ERK2, PI3K, Akt, NF-κB, pSMAD2, pSMAD3, Src, Pyk2, FAK and/ or p-p130Cas. In case of an ophthalmic disease such as AMD or DME an oligonucleotide of the present invention may be combined with an anti-VEGF antibody or an antagonistic protein such as a fusion protein, laser therapy and/or a corticosteroid such as cortisol (C21H30O5), corticosterone (C21H30O4), cortisone (C21H28O5) and/or aldosterone (C21H28O5). A subject of the present invention is for example a mammalian (e.g., a human, monkey, dog, cat horse, cow, pig), bird, or fish. Examples The following examples illustrate different embodiments of the present invention, but the invention is not limited to these examples. Example 1: Design of human, mouse and rat NRP1 antisense oligonucleotides For the design of ASOs with specificity for exonic regions within the human NRP1 gene the NRP1 mRNA sequence with the RefSeq ID NM_003873.6 (SEQ ID NO.367; Fig. 1) was used. For ASOs with specificity for intronic regions within the human NRP1 gene the NRP1 pre-mRNA sequence (GRCh38p13_Chr 10_33177492-1 (SEQ ID NO.366) was used. An “H” after the ASO ID indicates a human NRP1-specific sequence that binds to an exonic region of the pre-mRNA, a “HMI” after the ASO ID indicates a human / mouse cross-reactive NRP1 sequence that binds to an intronic region of the pre-mRNA and a “HI” after the ASO ID indicates a human NRP1-specific sequence that binds to an intronic region of the pre-mRNA. 15, 16, 17, 18, 19, and 20 mers were designed according to in house criteria, neg1 (described in WO2014/154843 A1) was used as control oligonucleotide in all experiments (e.g., for Table 1). Example 2: Target knockdown efficacy screen of human NRP1-specific ASOs In order to investigate the knockdown efficacy of the in silico designed NRP1-specific ASOs, three efficacy screening rounds in human cell lines were performed. Therefore, cells were treated with the respective ASO at a concentration of 5 µM for three days without the addition of a transfection reagent. Cells were lysed after the three days treatment period, NRP1 and HPRT1 mRNA expression was analyzed using the QuantiGene Singleplex assay (ThermoFisher) and the NRP1 expression values were normalized to HPRT1 values and compared to mock-treated samples. The results are shown in Fig. 3, Fig. 4, and Fig.5 as well as in Table 5, 6, and 7. As depicted in Fig.3 and Table 5, treatment of SKOV-3 cells with 160 of the 398 tested ASOs (0.2%) resulted in a target inhibition of >50 % (represented by a residual NRP1 mRNA expression of <0.5 as compared to mock treated cells). ASO Residual NRP1 ASO Residual NRP1 expression expression (compared to mock (compared to mock treated cells) treated cells) A15091HI 0.03 A15401HI 0.59 A15473HI 0.07 A15271HI 0.59 A15466HI 0.08 A15451H 0.59 A15340HI 0.08 A15158HI 0.60 A15256HI 0.08 A15407H 0.60 A15492HI 0.09 A15146HI 0.60 A15467HI 0.09 A15453H 0.60 A15378HI 0.09 A15270HI 0.61 A15144HI 0.10 A15459H 0.61 A15262HI 0.10 A15125HI 0.61 A15217HI 0.10 A15143HI 0.61 A15465HI 0.11 A15382HI 0.62 A15496HI 0.13 A15301HI 0.62 A15505HI 0.13 A15152HI 0.62 A15417HI 0.13 A15449HI 0.63 A15493HI 0.14 A15130HI 0.63 A15508HI 0.15 A15147HI 0.63 A15219HI 0.16 A15218HI 0.63 A15396HI 0.16 A15457H 0.63 A15088HI 0.16 A15358HI 0.64 A15108HI 0.16 A15337H 0.64 A15403HI 0.17 A15274HI 0.64 A15228HI 0.17 A15204H 0.64 A15092HI 0.17 A15307HI 0.65 A15507HI 0.17 A15207H 0.65 A15500HI 0.17 A15229HI 0.65 A15110HI 0.18 A15463H 0.65 A15131HI 0.18 A15265HI 0.65 A15111HI 0.18 A15371H 0.66 A15504HI 0.18 A15367HI 0.66 A15476HI 0.18 A15292HI 0.66 A15430HI 0.18 A15447H 0.66 A15134HI 0.18 A15343H 0.66 A15491HI 0.19 A15399HI 0.66 A15501HI 0.19 A15321HI 0.66 A15257HI 0.19 A15104HI 0.66 A15502HI 0.20 A15335H 0.66 A15119HI 0.20 A15360HI 0.66 A15255HI 0.20 A15421HI 0.66 A15350H 0.20 A15328HI 0.67 A15395H 0.20 A15244HI 0.67 A15488HI 0.21 A15319HI 0.67 A15227HI 0.22 A15273HI 0.68 A15383HI 0.22 A15150HI 0.68 A15418HI 0.22 A15298HI 0.68 A15469HI 0.23 A15282HI 0.68 A15261HI 0.23 A15157HI 0.68 A15499HI 0.23 A15345HI 0.69 A15380HI 0.24 A15455H 0.69 A15489HI 0.24 A15314HI 0.70 A15497HI 0.24 A15234HI 0.70 A15109HI 0.24 A15377HI 0.70 A15402HI 0.25 A15303HI 0.70 A15115HI 0.25 A15193H 0.70 A15129HI 0.25 A15397HI 0.70 A15509HI 0.25 A15252HI 0.70 A15093HI 0.25 A15098HI 0.70 A15511HI 0.26 A15414H 0.70 A15432HI 0.26 A15203H 0.70 A15137HI 0.26 A15241HI 0.71 A15127HI 0.26 A15233HI 0.71 A15506HI 0.26 A15199H 0.71 A15105HI 0.26 A15361HI 0.71 A15503HI 0.27 A15435HI 0.71 A15120HI 0.27 A15138HI 0.71 A15246HI 0.27 A15310HI 0.72 A15232HI 0.27 A15286HI 0.72 A15423HI 0.28 A15331HI 0.72 A15235HI 0.28 A15400HI 0.73 A15370H 0.29 A15336H 0.73 A15142HI 0.29 A15318HI 0.73 A15364HI 0.29 A15338HI 0.73 A15472HI 0.30 A15225HI 0.73 A15210H 0.30 A15284HI 0.73 A15095HI 0.30 A15242HI 0.73 A15249HI 0.30 A15322HI 0.74 A15490HI 0.31 A15353HI 0.74 A15443HI 0.31 A15312HI 0.74 A15254HI 0.31 A15436HI 0.74 A15224HI 0.32 A15412HI 0.74 A15388HI 0.32 A15164HI 0.74 A15495HI 0.32 A15327HI 0.75 A15087HI 0.32 A15306HI 0.75 A15313HI 0.32 A15416H 0.75 A15384HI 0.32 A15325HI 0.75 A15365HI 0.32 A15266HI 0.75 A15372HI 0.34 A15323HI 0.75 A15253HI 0.34 A15386HI 0.75 A15149HI 0.34 A15389HI 0.76 A15444HI 0.34 A15460H 0.76 A15136HI 0.34 A15315HI 0.76 A15347HI 0.34 A15398HI 0.76 A15245HI 0.35 A15278HI 0.76 A15461H 0.35 A15182HI 0.76 A15390HI 0.36 A15258HI 0.77 A15154HI 0.36 A15408H 0.77 A15121HI 0.37 A15184HI 0.78 A15205H 0.37 A15320HI 0.78 A15162HI 0.37 A15391HI 0.78 A15269HI 0.37 A15446H 0.78 A15498HI 0.37 A15237HI 0.78 A15433HI 0.37 A15173HI 0.78 A15096HI 0.38 A15160HI 0.79 A15471HI 0.38 A15097HI 0.79 A15341HI 0.38 A15309HI 0.79 A15090HI 0.39 A15410HI 0.80 A15222HI 0.39 A15145HI 0.81 A15468HI 0.39 A15375HI 0.81 A15357HI 0.39 A15175HI 0.81 A15251HI 0.39 A15089HI 0.81 A15349HI 0.39 A15288HI 0.82 A15346HI 0.40 A15272HI 0.82 A15106HI 0.40 A15445HI 0.83 A15208H 0.40 A15276HI 0.83 A15379HI 0.40 A15167HI 0.83 A15141HI 0.40 A15202H 0.83 A15420HI 0.41 A15263HI 0.84 A15356HI 0.41 A15311HI 0.84 A15122HI 0.41 A15166HI 0.84 A15236HI 0.41 A15168HI 0.84 A15259HI 0.41 A15281HI 0.86 A15140HI 0.41 A15279HI 0.86 A15099HI 0.41 A15264HI 0.86 A15305HI 0.41 A15293HI 0.86 A15153HI 0.42 A15302HI 0.87 A15494HI 0.42 A15165HI 0.87 A15434HI 0.42 A15176HI 0.87 A15413HI 0.42 A15339HI 0.88 A15510HI 0.42 A15409HI 0.89 A15411HI 0.42 A15333HI 0.89 A15148HI 0.43 A15283HI 0.90 A15126HI 0.43 A15289HI 0.90 A15103HI 0.44 A15297HI 0.91 A15369H 0.44 A15177HI 0.91 A15239HI 0.44 A15454H 0.91 A15354HI 0.45 A15231HI 0.91 A15431HI 0.45 A15429HI 0.91 A15117HI 0.45 A15183HI 0.92 A15363HI 0.45 A15287HI 0.92 A15248HI 0.46 A15440HI 0.92 A15351H 0.46 A15285HI 0.92 A15238HI 0.46 A15178HI 0.93 A15394H 0.46 A15448H 0.93 A15428HI 0.47 Neg1 0.93 A15464H 0.47 A15299HI 0.94 A15124HI 0.47 A15374H 0.94 A15450H 0.48 A15194H 0.94 A15344HI 0.48 A15441HI 0.95 A15393H 0.48 A15458H 0.95 A15132HMI 0.48 A15373HI 0.96 A15211H 0.48 A15163HI 0.96 A15221HI 0.48 A15267HI 0.96 A15275HI 0.48 A15425HI 0.97 A15366HI 0.48 A15326HI 0.97 A15308HI 0.49 A15240HI 0.97 A15128HI 0.49 A15438H 0.98 A15424HI 0.49 A15172HI 0.99 A15216H 0.49 A15268HI 0.99 A15334H 0.49 A15348HI 0.99 A15470HI 0.49 A15171HI 1.00 A15226HI 0.50 A15220HI 1.02 A15342H 0.50 A15170HI 1.02 A15102HI 0.50 A15317HI 1.02 A15223HI 0.50 A15291HI 1.04 A15405H 0.50 A15442HI 1.05 A15201H 0.51 A15376HI 1.05 A15159HI 0.51 A15300HI 1.05 A15437HI 0.51 A15296HI 1.05 A15427HI 0.51 A15188H 1.06 A15277HI 0.52 A15181HI 1.07 A15113HI 0.52 A15330HI 1.08 A15422HI 0.52 A15290HI 1.08 A15362HI 0.52 A15260HI 1.08 A15243HI 0.52 A15169HI 1.08 A15406H 0.52 A15195H 1.09 A15392H 0.53 A15294HI 1.09 A15116HI 0.53 A15250HI 1.10 A15139HI 0.53 A15197H 1.10 A15304HI 0.53 A15415H 1.11 A15332HI 0.53 A15439HI 1.12 A15385HI 0.54 A15212H 1.13 A15123HI 0.54 A15185HI 1.16 A15368HI 0.54 A15174HI 1.16 A15381HI 0.54 A15316HI 1.18 A15230HI 0.54 A15247HI 1.18 A15329HI 0.54 A15209H 1.19 A15452H 0.55 A15186HMI 1.20 A15426HI 0.55 A15295HI 1.21 A15100HI 0.55 A15189H 1.22 A15387HI 0.55 A15215H 1.24 A15200H 0.55 A15190H 1.29 A15280HI 0.56 A15191H 1.31 A15419HI 0.57 A15187H 1.34 A15359HI 0.57 A15192H 1.48 A15324HI 0.57 A15196H 1.76 A15352H 0.58 A15206H 1.84 A15155HI 0.59 A15214H 3.69 A15355HI 0.59 A15213H 4.03 A15462H 0.59 A15198H 8.20 Table 5: List of the mean NRP1 mRNA expression values in ASO-treated SKOV-3 cells compared to mock treated cells. Expression values are normalized to HPRT1. Knockdown efficacy of NRP1-specific ASOs was furthermore tested in U87-MG cells. As shown in Fig. 4 and Table 6, treatment with 38 of the 120 tested ASOs (31.7%) resulted in a target inhibition of >50 % (represented by a residual NRP1 mRNA expression of <0.5 as compared to mock treated cells). ASO Residual NRP1 ASO Residual NRP1 expression expression (compared to mock (compared to mock treated cells) treated cells) A15191H 0.10 A15177HI 0.64 A15144HI 0.15 A15129HI 0.65 A15146HI 0.15 A15113HI 0.65 A15091HI 0.18 A15173HI 0.65 A15194H 0.21 A15178HI 0.66 A15159HI 0.22 A15103HI 0.67 A15166HI 0.24 A15209H 0.69 A15136HI 0.27 A15148HI 0.70 A15193H 0.27 A15186HMI 0.70 A15169HI 0.29 A15203H 0.70 A15198H 0.30 A15147HI 0.71 A15140HI 0.30 A15195H 0.71 A15152HI 0.30 A15149HI 0.71 A15119HI 0.32 A15154HI 0.71 A15168HI 0.32 A15157HI 0.71 A15108HI 0.33 A15182HI 0.71 A15093HI 0.34 A15187H 0.72 A15196H 0.34 A15216H 0.72 A15134HI 0.34 A15095HI 0.73 A15171HI 0.35 A15139HI 0.73 A15105HI 0.37 A15167HI 0.73 A15183HI 0.37 A15138HI 0.74 A15205H 0.38 A15204H 0.75 A15172HI 0.39 A15189H 0.76 A15200H 0.39 A15143HI 0.76 A15192H 0.42 A15116HI 0.77 A15106HI 0.43 R01011 0.77 A15185HI 0.44 A15207H 0.77 A15099HI 0.46 A15098HI 0.77 A15087HI 0.46 A15199H 0.78 A15137HI 0.46 A15165HI 0.78 A15120HI 0.47 A15121HI 0.78 A15184HI 0.48 A15132HMI 0.79 A15201H 0.48 A15150HI 0.81 A15170HI 0.48 A15160HI 0.81 A15092HI 0.48 A15155HI 0.82 A15213H 0.49 A15115HI 0.82 A15110HI 0.49 A15128HI 0.83 A15212H 0.50 A15089HI 0.83 A15126HI 0.50 A15164HI 0.83 A15210H 0.50 A15102HI 0.84 A15162HI 0.51 A15097HI 0.85 A15153HI 0.52 A15145HI 0.87 A15111HI 0.52 A15188H 0.88 A15131HI 0.52 A15122HI 0.88 A15190H 0.54 A15104HI 0.89 A15100HI 0.56 A15088HI 0.89 A15208H 0.57 A15090HI 0.90 A15142HI 0.58 A15125HI 0.91 A15109HI 0.58 A15124HI 0.93 A15197H 0.59 A15117HI 0.94 A15158HI 0.60 A15181HI 0.95 A15211H 0.60 A15174HI 0.95 A15206H 0.60 neg1 0.98 A15215H 0.60 A15130HI 0.99 A15214H 0.60 A15175HI 1.02 A15127HI 0.61 A15163HI 1.03 A15141HI 0.61 A15123HI 1.04 A15202H 0.62 R01002 1.06 A15096HI 0.62 A15176HI 1.10 Table 6: List of the mean NRP1 mRNA expression values in ASO-treated U87-MG cells compared to mock treated cells. Expression values are normalized to HPRT1. Knockdown efficacy of NRP1-specific ASOs was furthermore tested in Panc1 cells. As shown in Fig. 5 and Table 7, treatment with 154 of the 257 tested ASOs (59.9%) resulted in a target inhibition of >50 % (represented by a residual NRP1 mRNA expression of <0.5 as compared to mock treated cells). The control oligo did not result in an inhibition of NRP1 expression in any of the three cell lines. ASO Residual NRP1 ASO Residual NRP1 expression expression (compared to mock (compared to mock treated cells) treated cells) A15383HI 0.00 A15435HI 0.41 A15380HI 0.01 A15298HI 0.41 A15473HI 0.01 A15322HI 0.41 A15467HI 0.02 A15342H 0.42 A15217HI 0.03 A15434HI 0.43 A15466HI 0.03 A15393H 0.43 A15469HI 0.03 A15265HI 0.43 A15262HI 0.04 A15428HI 0.43 A15228HI 0.05 A15234HI 0.44 A15350H 0.06 A15270HI 0.44 A15219HI 0.06 A15427HI 0.44 A15378HI 0.06 A15274HI 0.44 A15257HI 0.07 A15241HI 0.44 A15388HI 0.07 A15317HI 0.44 A15423HI 0.08 A15353HI 0.44 A15327HI 0.08 A15275HI 0.45 A15396HI 0.08 A15331HI 0.45 A15470HI 0.08 A15237HI 0.46 A15471HI 0.08 A15392H 0.47 A15465HI 0.08 A15271HI 0.47 A15417HI 0.08 A15243HI 0.47 A15227HI 0.09 A15244HI 0.48 A15235HI 0.10 A15358HI 0.48 A15256HI 0.10 A15362HI 0.48 A15224HI 0.10 A15459H 0.49 A15387HI 0.10 A15447H 0.50 A15402HI 0.10 A15277HI 0.50 A15347HI 0.11 A15273HI 0.50 A15472HI 0.11 A15406H 0.51 A15222HI 0.11 A15314HI 0.51 A15395H 0.12 A15414H 0.53 A15340HI 0.12 A15449HI 0.53 A15261HI 0.13 A15250HI 0.53 A15253HI 0.13 A15316HI 0.55 A15451H 0.13 A15361HI 0.55 A15223HI 0.14 A15407H 0.56 A15403HI 0.14 A15438H 0.56 A15476HI 0.14 A15264HI 0.57 A15349HI 0.14 A15304HI 0.57 A15418HI 0.15 A15394H 0.57 A15468HI 0.15 A15229HI 0.57 A15341HI 0.15 A15389HI 0.57 A15432HI 0.15 A15231HI 0.57 A15246HI 0.16 A15375HI 0.58 A15364HI 0.16 A15343H 0.58 A15453H 0.16 A15225HI 0.58 A15221HI 0.16 A15248HI 0.58 A15430HI 0.16 A15299HI 0.58 A15379HI 0.17 A15367HI 0.58 A15269HI 0.17 A15445HI 0.59 A15238HI 0.17 A15290HI 0.59 A15334H 0.18 A15315HI 0.60 A15259HI 0.18 A15266HI 0.60 A15255HI 0.18 A15436HI 0.62 A15323HI 0.18 A15371H 0.64 A15452H 0.18 A15408H 0.65 A15232HI 0.18 A15319HI 0.65 A15313HI 0.18 A15360HI 0.65 A15420HI 0.18 A15440HI 0.65 A15230HI 0.18 A15416H 0.65 A15236HI 0.19 A15302HI 0.66 A15356HI 0.19 A15282HI 0.66 A15326HI 0.19 A15460H 0.67 A15370H 0.19 A15397HI 0.67 A15332HI 0.19 A15310HI 0.68 A15411HI 0.20 A15283HI 0.68 A15325HI 0.20 A15267HI 0.68 A15351H 0.20 A15258HI 0.70 A15239HI 0.20 A15307HI 0.71 A15324HI 0.21 A15284HI 0.71 A15443HI 0.22 A15303HI 0.72 A15372HI 0.22 A15306HI 0.73 A15352H 0.22 A15276HI 0.73 A15464H 0.23 A15373HI 0.73 A15381HI 0.24 A15337H 0.74 A15433HI 0.24 A15320HI 0.74 A15346HI 0.24 A15285HI 0.76 A15444HI 0.24 A15330HI 0.76 A15357HI 0.26 A15410HI 0.76 A15458H 0.26 A15293HI 0.77 A15384HI 0.26 A15278HI 0.77 A15363HI 0.26 A15233HI 0.77 A15254HI 0.26 A15291HI 0.77 A15401HI 0.27 A15301HI 0.78 A15454H 0.27 A15391HI 0.78 A15251HI 0.27 A15286HI 0.80 A15431HI 0.27 A15272HI 0.80 A15365HI 0.27 A15442HI 0.81 A15419HI 0.28 A15412HI 0.81 A15333HI 0.28 A15287HI 0.82 A15437HI 0.28 A15300HI 0.82 A15321HI 0.28 A15220HI 0.82 A15245HI 0.28 A15268HI 0.83 A15226HI 0.28 A15441HI 0.85 A15355HI 0.29 A15297HI 0.85 A15413HI 0.29 A15409HI 0.86 A15386HI 0.29 A15288HI 0.87 A15218HI 0.30 A15279HI 0.87 A15461H 0.30 A15336H 0.88 A15344HI 0.30 A15348HI 0.89 A15329HI 0.30 A15345HI 0.92 A15457H 0.30 A15294HI 0.92 A15318HI 0.30 A15335H 0.94 A15369H 0.31 A15429HI 0.94 A15382HI 0.32 A15448H 0.95 A15455H 0.32 A15415H 0.95 A15366HI 0.32 A15289HI 0.96 A15422HI 0.32 A15425HI 0.98 A15359HI 0.33 A15374H 0.99 A15399HI 0.33 A15263HI 1.00 A15249HI 0.33 A15281HI 1.00 A15305HI 0.34 A15404H 1.00 A15424HI 0.34 A15252HI 1.03 A15450H 0.35 A15311HI 1.09 A15328HI 0.35 Neg1 1.10 A15400HI 0.35 A15296HI 1.11 A15280HI 0.36 A15339HI 1.12 A15390HI 0.36 A15338HI 1.16 A15385HI 0.37 A15446H 1.16 A15242HI 0.37 A15240HI 1.16 A15354HI 0.38 A15398HI 1.21 A15309HI 0.38 A15295HI 1.25 A15463H 0.38 A15376HI 1.25 A15426HI 0.38 A15312HI 1.29 A15368HI 0.39 A15260HI 1.34 A15462H 0.39 A15439HI 1.34 A15421HI 0.39 A15377HI 1.47 A15308HI 0.40 A15247HI 1.80 A15292HI 0.40 Table 7: List of the mean NRP1 mRNA expression values in ASO-treated Panc1 cells compared to mock treated cells. Expression values are normalized to HPRT1. Example 3: Investigation of target knockdown by selected human NRP1-specific ASOs in CD4⁺ T cells 9 of the human NRP1-specific ASOs were selected in order to investigate the knockdown efficacy of NRP1-specific ASOs in human CD4⁺ T cells cultured under conditions to preferentially activate and expand Tregs. Therefore, CD4⁺ T cells were isolated from PBMC and treated with the indicated ASOs for three days at a concentration of 5 µM. As shown in Fig.6, a knockdown of NRP1 >40 % was observed with 8 of the 9 (88.9%) tested ASOs compared to mock-treated cells. In contrast, treatment with the control oligo had no negative effect on NRP1 expression. Residual NRP1 Residual NRP1 expression expression ASO ASO (compared to mock (compared to mock treated cells) treated cells) A15091HI 0.08 A15159HI 0.54 A15144HI 0.24 A15166HI 0.57 A15108HI 0.41 A15169HI 0.59 A15134HI 0.50 A15110HI 0.69 A15194H 0.53 Neg1 1.82 Table 8: List of the mean NRP1 mRNA expression values in ASO-treated CD4⁺ T cells compared to mock treated cells. Expression values are normalized to HPRT1. Example 4: Investigation of the concentration-dependent target knockdown by selected human NRP1-specific ASOs The concentration-dependent knockdown of NRP1 mRNA expression by NRP1-specific ASOs was investigated in SKOV-3 cells and CD4⁺ T cells on mRNA level and the respective IC50 values were calculated. Therefore, SKOV-3 cells were treated for three days with the respective ASO at the following concentrations: 5000 nM, 1667 nM, 556 nM, 185 nM, 62 nM, 21 nM and 7 nM. CD4⁺ T cells were treated for three days with the respective ASO at the same concentrations. After the treatment period, cells were lysed, NRP1 and HPRT1 mRNA expression was analyzed using the QuantiGene Singleplex assay (ThermoFisher) and the NRP1 expression values were normalized to HPRT1 values and compared to mock-treated samples (Fig.7 and Fig. 8 as well as Tables 9 and 10). A concentration-dependent knockdown of NRP1 mRNA after treatment with all tested NRP1-specific ASOs in SKOV-3 (Fig. 7) and CD4⁺ T cells (Fig. 8) was observed with IC50 values between 119 nM (A15091HI in SKOV-3 cells, Table 9) and 1101 nM (A15166HI in CD4+ T cells, Table 10). Inhibition (%) ASO IC50 7 nM 21 nM 62 nM 185 nM 556 nM 1.6 µM 5 µM (nM) A15091HI 119 16.9 31.5 33.2 48.5 69.9 87.5 97 A15108HI 171 -4.9 -40.1 33.8 47.7 69.2 87.4 94.2 A15219HI 131 0.6 13.2 36.8 50.9 67.5 82.6 90.7 A15228HI 210 3 7.7 22.2 43 53.5 74.9 84.4 A15257HI 240 -3.9 12 12.5 39.8 60.4 74.4 86.3 A15262HI 139 19.3 12.4 26.1 50 69.3 82.2 89.8 A15378HI 323 ND 11.7 10.5 29.8 61.7 78.2 92.2 A15403HI 338 -1.9 0.6 18.6 24.4 57.4 75.8 88 A15430HI 233 ND 1.7 16.8 40 62 78.3 87.7 A15466H 229 -4.6 6.4 21.9 38.6 67.5 86.1 93.5 Table 9: Concentration-dependent inhibition of NRP1 mRNA expression in SKOV-3 cells by selected NRP1-specific ASOs and respective IC50 values. ND = Not determined. Inhibition (%) ASO IC50 (nM) 7 nM 21 nM 62 nM 185 nM 556 nM 1.67 µM 5 µM A15091HI 424 -41,0 -40,9 -3,5 25,8 53,2 84,9 91,6 A15108HI 698 -66,9 -30,1 -8,3 2,2 29,1 36,4 57,8 A15110HI 448 -33,7 -46,1 -12,3 15,1 33,8 55,4 59,0 A15134HI 981 ND -21,7 -20,9 -7,4 21,3 33,5 52,6 A15144HI 244 -20,6 -11,0 -6,7 37,5 66,4 79,2 92,2 A15159HI 1004 -52,5 -41,6 -31,2 -4,3 22,3 45,4 66,6 A15166HI 1101 -49,4 -33,0 -18,0 -10,3 19,3 38,2 58,6 A15169HI 521 ND -5,2 -31,6 9,0 29,7 32,1 55,1 A15194H 202 ND 4,2 25,9 47,6 43,5 65,9 74,5 Table 10: Concentration-dependent inhibition of NRP1 mRNA expression in CD4+ T cells by selected NRP1-specific ASOs and respective IC50 values. ND = Not determined. Example 5: Investigation of acute toxicity of human NRP1-specific ASOs In order to determine the acute toxicity of the antisense oligonucleotide A15005HMR (SEQ ID NO.368, described in US20190330640A1), and of the antisense oligonucleotides A15091HI (SEQ ID NO.5), A15108HI (SEQ ID NO.19) and A15166HI (SEQ ID NO.69) of the present invention, female Balb/c mice were subcutaneously injected with selected human NRP1-specific ASOs on five consecutive days at a dose of 20 mg per kg of body weight. General appearance was monitored daily and the serological parameters ALAT (alanine-aminotransferase), ASAT (aspartate transferase) and LDH (lactate dehydrogenase) were analyzed on days 5, 9 and 12, depicted in Fig. 9. Almost no increase of ALAT, ASAT or LDH has been observed after treatment of mice with ASOs from the present invention, whereas substantial increases were seen in mice treated with A15005HMR. Furthermore, the mice treated with A15005HMR all died before the second measurement on day 9 whereas none of the mice died that had been treated with ASOs from the present invention. Example 6: In silico analysis of potential off-target binding sites The results of the in silico analysis are shown in the following Table 11: RefSeq Gene IDs Ensembl Name (ASO ID) 0 mm 1 mm 2 mm 0 mm 1 mm 2 mm A15087HI 0 0 27 0 0 126 A15088HI 0 0 19 0 0 107 A15089HI 0 0 13 0 0 97 A15090HI 0 0 15 0 0 155 A15091HI 0 0 9 0 0 133 A15092HI 0 0 16 0 0 124 A15093HI 0 0 10 0 0 63 A15095HI 0 0 2 0 0 41 A15096HI 0 0 7 0 0 71 A15097HI 0 0 15 0 0 45 A15098HI 0 0 12 0 0 106 A15099HI 0 0 9 0 0 123 A15100HI 0 0 8 0 0 71 A15102HI 0 0 19 0 0 119 A15103HI 0 0 8 0 0 125 A15104HI 0 0 5 0 0 58 A15105HI 0 0 2 0 0 31 A15106HI 0 0 3 0 0 29 A15108HI 0 0 10 0 0 126 A15109HI 0 0 11 0 0 122 A15110HI 0 0 4 0 0 30 A15111HI 0 0 8 0 0 102 A15113HI 0 0 4 0 0 94 A15115HI 0 0 0 0 0 20 A15116HI 0 0 1 0 0 43 A15117HI 0 0 0 0 0 15 A15119HI 0 0 2 0 0 26 A15120HI 0 0 2 0 0 44 A15121HI 0 0 0 0 0 19 A15122HI 0 0 0 0 0 44 A15123HI 0 0 4 0 0 52 A15124HI 0 0 0 0 0 77 A15125HI 0 0 4 0 0 99 A15126HI 0 0 0 0 0 48 A15127HI 0 0 3 0 0 74 A15128HI 0 0 0 0 0 8 A15129HI 0 0 0 0 0 10 A15130HI 0 0 0 0 0 30 A15131HI 0 0 0 0 0 23 A15132HMI 0 0 6 0 0 71 A15134HI 0 0 3 0 0 53 A15136HI 0 0 1 0 0 13 A15137HI 0 0 0 0 0 23 A15138HI 0 0 2 0 0 67 A15139HI 0 0 3 0 0 41 A15140HI 0 0 2 0 0 47 A15141HI 0 0 1 0 0 40 A15142HI 0 0 0 0 0 42 A15143HI 0 0 0 0 0 33 A15144HI 0 0 4 0 0 57 A15145HI 0 0 4 0 0 52 A15146HI 0 0 1 0 0 51 A15147HI 0 0 1 0 0 25 A15148HI 0 0 0 0 0 8 A15149HI 0 0 0 0 0 6 A15150HI 0 0 0 0 0 7 A15152HI 0 0 1 0 0 54 A15153HI 0 0 0 0 0 19 A15154HI 0 0 1 0 0 28 A15155HI 0 0 0 0 0 37 A15157HI 0 0 1 0 0 26 A15158HI 0 0 5 0 0 38 A15159HI 0 0 5 0 0 33 A15160HI 0 0 1 0 0 57 A15162HI 0 0 0 0 0 2 A15163HI 0 0 0 0 0 9 A15164HI 0 0 4 0 0 54 A15165HI 0 0 2 0 0 44 A15166HI 0 0 0 0 0 7 A15167HI 0 0 0 0 0 23 A15168HI 0 0 4 0 0 69 A15169HI 0 0 1 0 0 21 A15170HI 0 0 0 0 0 19 A15171HI 0 0 0 0 0 8 A15172HI 0 0 3 0 0 36 A15173HI 0 0 0 0 0 21 A15174HI 0 0 4 0 0 45 A15175HI 0 0 2 0 0 77 A15176HI 0 0 3 0 0 55 A15177HI 0 0 1 0 0 61 A15178HI 0 0 1 0 0 20 A15181HI 0 0 4 0 0 58 A15182HI 0 0 3 0 0 49 A15183HI 0 0 1 0 0 38 A15184HI 0 0 0 0 0 37 A15185HI 0 0 0 0 0 29 A15186HMI 0 0 1 0 0 47 A15187H 0 0 1 0 0 17 A15188H 0 0 0 0 0 13 A15189H 0 0 1 0 0 9 A15190H 0 0 0 0 0 1 A15191H 0 0 5 0 0 37 A15192H 0 0 0 0 0 11 A15193H 0 0 9 0 0 33 A15194H 0 0 5 0 0 17 A15195H 0 0 2 0 0 16 A15196H 0 0 0 0 0 8 A15197H 0 0 4 0 0 26 A15198H 0 0 0 0 0 22 A15199H 0 0 4 0 0 33 A15200H 0 0 5 0 0 35 A15201H 0 0 3 0 0 31 A15202H 0 0 3 0 0 21 A15203H 0 0 0 0 0 12 A15204H 0 0 7 0 0 39 A15205H 0 0 8 0 0 50 A15206H 0 0 7 0 0 48 A15207H 0 0 1 0 0 19 A15208H 0 0 1 0 0 35 A15209H 0 0 3 0 0 28 A15210H 0 0 2 0 0 28 A15211H 0 0 1 0 0 24 A15212H 0 0 4 0 0 39 A15213H 0 0 3 0 0 39 A15214H 0 0 2 0 0 22 A15215H 0 0 2 0 0 34 A15216H 0 0 9 0 0 49 A15217HI 0 0 1 0 0 1 A15218HI 0 0 1 0 0 11 A15219HI 0 0 1 0 0 3 A15220HI 0 0 1 0 0 14 A15221HI 0 0 5 0 0 59 A15222HI 0 0 1 0 0 6 A15223HI 0 0 1 0 0 4 A15224HI 0 0 1 0 0 5 A15225HI 0 0 1 0 0 14 A15226HI 0 0 3 0 0 17 A15227HI 0 0 1 0 0 2 A15228HI 0 0 1 0 0 7 A15229HI 0 0 1 0 0 22 A15230HI 0 0 1 0 0 5 A15231HI 0 0 2 0 0 10 A15232HI 0 0 4 0 0 50 A15233HI 0 0 1 0 0 22 A15234HI 0 0 2 0 0 7 A15235HI 0 0 1 0 0 8 A15236HI 0 0 2 0 0 28 A15237HI 0 0 2 0 0 8 A15238HI 0 0 1 0 0 15 A15239HI 0 0 1 0 0 21 A15240HI 0 0 1 0 0 13 A15241HI 0 0 1 0 0 5 A15242HI 0 0 2 0 0 11 A15243HI 0 0 1 0 0 9 A15244HI 0 0 1 0 0 14 A15245HI 0 0 1 0 0 5 A15246HI 0 0 1 0 0 6 A15247HI 0 0 1 0 0 13 A15248HI 0 0 2 0 0 8 A15249HI 0 0 2 0 0 7 A15250HI 0 0 1 0 0 12 A15251HI 0 0 1 0 0 9 A15252HI 0 0 1 0 0 5 A15253HI 0 0 1 0 0 4 A15254HI 0 0 1 0 0 3 A15255HI 0 0 1 0 0 32 A15256HI 0 0 0 0 0 3 A15257HI 0 0 0 0 0 25 A15258HI 0 0 1 0 0 10 A15259HI 0 0 1 0 0 5 A15260HI 0 0 2 0 0 12 A15261HI 0 0 1 0 0 3 A15262HI 0 0 2 0 0 4 A15263HI 0 0 2 0 0 7 A15264HI 0 0 1 0 0 23 A15265HI 0 0 1 0 0 2 A15266HI 0 0 2 0 0 43 A15267HI 0 0 1 0 0 4 A15268HI 0 0 1 0 0 12 A15269HI 0 0 1 0 0 5 A15270HI 0 0 2 0 0 17 A15271HI 0 0 11 0 0 72 A15272HI 0 0 1 0 0 50 A15273HI 0 0 5 0 0 15 A15274HI 0 0 1 0 0 14 A15275HI 0 0 4 0 0 29 A15276HI 0 0 1 0 0 28 A15277HI 0 0 1 0 0 17 A15278HI 0 0 1 0 0 7 A15279HI 0 0 1 0 0 20 A15280HI 0 0 1 0 0 3 A15281HI 0 0 1 0 0 14 A15282HI 0 0 1 0 0 18 A15283HI 0 0 3 0 0 11 A15284HI 0 0 3 0 0 8 A15285HI 0 0 1 0 0 8 A15286HI 0 0 1 0 0 6 A15287HI 0 0 1 0 0 7 A15288HI 0 0 1 0 0 6 A15289HI 0 0 2 0 0 4 A15290HI 0 0 8 0 0 50 A15291HI 0 0 1 0 0 4 A15292HI 0 0 2 0 0 25 A15293HI 0 0 1 0 0 14 A15294HI 0 0 2 0 0 8 A15295HI 0 0 1 0 0 9 A15296HI 0 0 1 0 0 1 A15297HI 0 0 1 0 0 15 A15298HI 0 0 1 0 0 2 A15299HI 0 0 1 0 0 2 A15300HI 0 0 13 0 0 94 A15301HI 0 0 0 0 0 21 A15302HI 0 0 1 0 0 5 A15303HI 0 0 1 0 0 3 A15304HI 0 0 1 0 0 5 A15305HI 0 0 1 0 0 4 A15306HI 0 0 1 0 0 46 A15307HI 0 0 1 0 0 6 A15308HI 0 0 1 0 0 4 A15309HI 0 0 1 0 0 8 A15310HI 0 0 1 0 0 15 A15311HI 0 0 2 0 0 18 A15312HI 0 0 2 0 0 16 A15313HI 0 0 1 0 0 8 A15314HI 0 0 2 0 0 17 A15315HI 0 0 2 0 0 4 A15316HI 0 0 2 0 0 26 A15317HI 0 0 2 0 0 22 A15318HI 0 0 1 0 0 10 A15319HI 0 0 1 0 0 10 A15320HI 0 0 1 0 0 8 A15321HI 0 0 1 0 0 6 A15322HI 0 0 1 0 0 26 A15323HI 0 0 1 0 0 11 A15324HI 0 0 0 0 0 20 A15325HI 0 0 1 0 0 6 A15326HI 0 0 1 0 0 10 A15327HI 0 0 1 0 0 8 A15328HI 0 0 1 0 0 2 A15329HI 0 0 1 0 0 7 A15330HI 0 0 1 0 0 17 A15331HI 0 0 1 0 0 14 A15332HI 0 0 2 0 0 5 A15333HI 0 0 1 0 0 7 A15334H 0 0 0 0 0 0 A15335H 0 0 0 0 0 3 A15336H 0 0 0 0 0 2 A15337H 0 0 1 0 0 7 A15338HI 0 0 2 0 0 14 A15339HI 0 0 5 0 0 19 A15340HI 0 0 5 0 0 35 A15341HI 0 0 1 0 0 2 A15342H 0 0 1 0 0 5 A15343H 0 0 0 0 0 3 A15344HI 0 0 2 0 0 31 A15345HI 0 0 1 0 0 2 A15346HI 0 0 1 0 0 37 A15347HI 0 0 5 0 0 32 A15348HI 0 0 3 0 0 11 A15349HI 0 0 7 0 0 156 A15350H 0 0 0 0 0 3 A15351H 0 0 1 0 0 13 A15352H 0 0 0 0 0 3 A15353HI 0 0 8 0 0 41 A15354HI 0 0 1 0 0 4 A15355HI 0 0 1 0 0 16 A15356HI 0 0 2 0 0 11 A15357HI 0 0 1 0 0 2 A15358HI 0 0 4 0 0 30 A15359HI 0 0 1 0 0 10 A15360HI 0 0 1 0 0 1 A15361HI 0 0 26 0 0 86 A15362HI 0 0 1 0 0 7 A15363HI 0 0 1 0 0 3 A15364HI 0 0 2 0 0 8 A15365HI 0 0 2 0 0 13 A15366HI 0 0 1 0 0 2 A15367HI 0 0 3 0 0 11 A15368HI 0 0 1 0 0 3 A15369H 0 0 0 0 0 9 A15370H 0 0 0 0 0 3 A15371H 0 0 0 0 0 1 A15372HI 0 0 1 0 0 2 A15373HI 0 0 1 0 0 5 A15374H 0 0 3 0 0 8 A15375HI 0 0 5 0 0 47 A15376HI 0 0 1 0 0 9 A15377HI 0 0 1 0 0 3 A15378HI 0 0 4 0 0 37 A15379HI 0 0 4 0 0 12 A15380HI 0 0 2 0 0 9 A15381HI 0 0 1 0 0 2 A15382HI 0 0 1 0 0 4 A15383HI 0 0 2 0 0 7 A15384HI 0 0 1 0 0 4 A15385HI 0 0 1 0 0 13 A15386HI 0 0 1 0 0 9 A15387HI 0 0 2 0 0 10 A15388HI 0 0 1 0 0 4 A15389HI 0 0 1 0 0 7 A15390HI 0 0 15 0 0 107 A15391HI 0 0 3 0 0 37 A15392H 0 0 0 0 0 0 A15393H 0 0 0 0 0 1 A15394H 0 0 3 0 0 11 A15395H 0 0 3 0 0 23 A15396HI 0 0 1 0 0 2 A15397HI 0 0 5 0 0 45 A15398HI 0 0 2 0 0 10 A15399HI 0 0 1 0 0 3 A15400HI 0 0 2 0 0 9 A15401HI 0 0 2 0 0 8 A15402HI 0 0 1 0 0 9 A15403HI 0 0 4 0 0 38 A15404H 0 0 2 0 0 7 A15406H 0 0 16 0 0 54 A15407H 0 0 2 0 0 20 A15408H 0 0 0 0 0 7 A15409HI 0 0 1 0 0 8 A15410HI 0 0 13 0 0 91 A15411HI 0 0 2 0 0 38 A15412HI 0 0 1 0 0 7 A15413HI 0 0 2 0 0 42 A15414H 0 0 2 0 0 4 A15415H 0 0 0 0 0 2 A15416H 0 0 2 0 0 4 A15417HI 0 0 1 0 0 8 A15418HI 0 0 3 0 0 6 A15419HI 0 0 1 0 0 12 A15420HI 0 0 3 0 0 34 A15421HI 0 0 1 0 0 2 A15422HI 0 0 3 0 0 12 A15423HI 0 0 1 0 0 1 A15424HI 0 0 1 0 0 10 A15425HI 0 0 1 0 0 9 A15426HI 0 0 1 0 0 1 A15427HI 0 0 3 0 0 37 A15428HI 0 0 1 0 0 8 A15429HI 0 0 5 0 0 25 A15430HI 0 0 3 0 0 9 A15431HI 0 0 1 0 0 2 A15432HI 0 0 1 0 0 10 A15433HI 0 0 5 0 0 27 A15434HI 0 0 2 0 0 45 A15435HI 0 0 1 0 0 2 A15436HI 0 0 1 0 0 3 A15437HI 0 0 2 0 0 2 A15438H 0 0 1 0 0 3 A15439HI 0 0 1 0 0 3 A15440HI 0 0 1 0 0 2 A15441HI 0 0 1 0 0 1 A15442HI 0 0 1 0 0 4 A15443HI 0 0 2 0 0 10 A15444HI 0 0 1 0 0 4 A15445HI 0 0 1 0 0 11 A15446H 0 0 1 0 0 8 A15447H 0 0 0 0 0 0 A15448H 0 0 0 0 0 6 A15449HI 0 0 1 0 0 3 A15450H 0 0 0 0 0 2 A15451H 0 0 0 0 0 3 A15452H 0 0 0 0 0 5 A15453H 0 0 4 0 0 35 A15454H 0 0 0 0 0 4 A15455H 0 0 0 0 0 0 A15457H 0 0 0 0 0 0 A15458H 0 0 2 0 0 4 A15459H 0 0 0 0 0 0 A15460H 0 0 1 0 0 4 A15461H 0 0 1 0 0 9 A15462H 0 0 0 0 0 3 A15463H 0 0 0 0 0 2 A15464H 0 0 0 0 0 2 A15465HI 0 0 3 0 0 55 Table 11: Number of non-target genes that have a complementary sequence to the respective NRP1-specific oligonucleotide, allowing 0, 1, or 2 mismatches. Based on either RefSeq or Ensembl sequences. Shown are the sequences contained in this invention and a sequence from Patent US20190330640A1 (A15005HMR: GTCTCAAGTCGCCTG (SEQ ID NO.368)) for comparison. Two different databases were screened in silico to test off-target effects of oligonucleotides of the present invention. These databases were RefSecRNA comprising sequences of spliced RNA and ENSEMBL comprising sequences of non-spliced RNA. The oligonucleotides shown in Table 11, except for A15005HMR, have no potential off-target binding site with zero mismatches, i.e., 100 % sequence complementarity (0mm) to an off-target sequence or one mismatch, i.e., ((n-1)/n*100) % sequence complementarity (1mm) to an off-target sequence. The number of potential off-target sites of an oligonucleotide of the present invention having two mismatches, i.e., ((n-2)/n*100) % sequence complementarity (2mm) is limited to max. 30 (see Table 11, RefSeq (Gene Ids), 2mm). Example 7: Concentration-dependent knockdown of NRP1 mRNA expression by NRP1- specific ASOs The concentration-dependent knockdown of NRP1 mRNA expression by NRP1-specific ASOs with the same underlying sequence but different LNA-modification pattern was investigated in Panc1 and SKOV-3 cells on the mRNA level and the respective IC50 values were calculated. Therefore, cells were treated for three days with the respective ASO (A15091HI (SEQ ID NO.5), A15486HI (SEQ ID NO.5), or A15487HI (SEQ ID NO.5), or Neg 1 control) at the following concentrations: 5000 nM, 1667 nM, 550 nM, 185 nM, 62 nM, 21 nM and 7 nM. After the treatment period, cells were lysed, NRP1 and HPRT1 mRNA expression was analyzed using the QuantiGene Singleplex assay (ThermoFisher) and the NRP1 expression values were normalized to HPRT1 values and compared to mock-treated samples (Fig. 10 and 11, and Table 13 and 14). A concentration-dependent knockdown of NRP1 mRNA was observed after treatment with all tested NRP1-specific ASOs in Panc1 (Fig. 10) and SKOV-3 cells (Fig.11) with IC50 values between 287 nM (A15486HI in Panc1 cells, Table 13) and 184 nM (A15486HI in SKOV-3 cells, Table 14). The following Table 12 shows a list of the mean NRP1 mRNA expression values in ASO- treated SKOV-3 cells compared to mock treated cells. Expression values are normalized to HPRT1: A^{SO Residual NRP1 expression} (_{compared to mock treated cells)} _A15486HI ^0.05 A_15479HI ^0.06 A_15487HI ^0.07 A_15091HI ^0.09 A15478HI 0.10 The following Table 13 shows a list of the mean NRP1 mRNA inhibition values and IC50 values in Panc1 cells treated with different concentrations of the respective ASO concentration-dependent inhibition of NRP1 mRNA expression in Panc1 cells by selected NRP1-specific ASOs and respective IC50 values: Inhibition (%) ASO IC50 (nM) 7 nM 21 nM 62 nM 185 nM 556 nM 1.67 µM 5 µM A15091HI 286 -3.5 1.5 0.1 36.1 70.9 92.1 98.6 A15486HI 287 4.9 11.1 12.8 36.3 69.6 88.0 95.7 A15487HI 275 4.2 4.5 14.8 42.4 68.1 91.2 98.1 The following Table 14 shows a list of the mean NRP1 mRNA inhibition values and IC50 values in SKOV-3 cells treated with different concentrations of the respective ASO concentration-dependent inhibition of NRP1 mRNA expression in Panc1 cells by selected NRP1-specific ASOs and respective IC50 values: Inhibition (%) ASO IC50 (nM) 7 nM 21 nM 62 nM 185 nM 556 nM 1.67 µM 5 µM A15091HI 250 12.4 15.8 22.6 49.3 70.7 88.1 96.8 A15486HI 184 16.7 8.9 27.1 54.6 72.7 88.2 95.3 A15487HI 263 1.7 -2.3 16.5 41.4 66.3 86.6 95.6

Claims

Claims 1. An oligonucleotide comprising 10 to 25 nucleotides, at least one nucleotide having a modification selected from the group consisting of a bridged nucleic acid such as LNA, ENA, cET, a 2'Fluoro modified nucleotide, a 2´O-Methyl modified nucleotide, a 2´O- Methoxyethyl modified nucleotide, a FANA and a combination thereof, and wherein the oligonucleotide hybridizes with a transcript or an mRNA of neuropilin 1 (NRP1) of SEQ ID NO.367 and/or with pre-mRNA of NRP1 of SEQ ID NO.366.

2. The oligonucleotide of claim 1, wherein the modification is located at the 5´-end and/or 3´-end of the oligonucleotide.

3. The oligonucleotide according to claim 1 or 2, wherein the oligonucleotide hybridizes outside a hybridizing active region or within a hybridizing active region of position 6450- 6749, 12150-12449, 134250-134549, 36150-36449, 17550-17849, 138750-139049, 32550- 32849 or a combination thereof.

4. The oligonucleotide according to any one of claims 1 to 3, wherein the oligonucleotide comprises SEQ ID NO.5, SEQ ID NO.120, SEQ ID NO.19, SEQ ID NO.163, SEQ ID NO.129, SEQ ID NO.364, SEQ ID NO.330, SEQ ID NO.158, SEQ ID NO.156 or a combination thereof.

5. The oligonucleotide according to any one of claims 1 to 4, wherein the oligonucleotide is selected from the group consisting of +A*+T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15091HI; SEQ ID NO:5), +T*+C*+G*T*T*G*G*A*A*A*T*G*C*C*A*T*+G*+C*+A (A15219HI; SEQ ID NO:120), +T*+A*+C*A*T*G*G*T*A*A*C*G*C*+C*+T*+T (A15108HI; SEQ ID NO:19), +A*+T*+A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G (A15486HI; SEQ ID NO:5), +A*+T*A*T*T*T*A*G*G*T*C*C*+A*+G*+C*+G (A15487HI; SEQ ID NO:5), +G*+G*+T*T*A*T*T*G*A*C*T*G*C*T*C*T*+C*+T*+A (A15262HI; SEQ ID NO:163), +G*+T*+T*T*C*C*T*T*A*G*C*T*T*A*G*T*+G*+C*+C (A15228HI; SEQ ID NO:129), +A*+A*T*+A*T*T*T*A*G*G*T*C*C*+A*G*+C*+G (A15466HI; SEQ ID NO:364), +G*+T*+T*A*C*T*C*C*G*T*T*C*C*T*T*+C*+A*+G (A15430HI; SQE ID NO:330), +T*+A*+G*G*T*A*C*G*A*G*C*A*T*+C*+G*+G (A15257HI; SQE ID NO:158), +A*+A*+T*A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15465HI; SEQ ID NO:364), +A*T*+A*T*T*T*A*G*G*T*C*C*A*+G*+C*+G (A15473HI; SEQ ID NO:5), +T*+T*+C*G*T*A*T*T*T*A*A*A*C*T*C*+T*+A*+C (A15255HI; SEQ ID NO:156) and a combination thereof, wherein + indicates an LNA nucleotide and * indicates a phosphorothioate (PTO) linkage between the nucleotides.

6. The oligonucleotide according to claim 4 or 5, wherein the oligonucleotide has 80 to 99 %, 85 to 98 %, 90 to 95 or 93 % sequence identity to any one of the oligonucleotides of SEQ ID NO.1 – SEQ ID NO.364.

7. The oligonucleotide according to any one of claims 4 to 6, wherein said oligonucleotide comprises at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 nucleotides of any one of the oligonucleotides of SEQ ID NO.1 – SEQ ID NO.364.

8. The oligonucleotide according to any one of claims 1 to 7, wherein the oligonucleotide inhibits the expression of NRP1, a NRP1 mRNA, a NRP1 pre-mRNA or a combination thereof at a nanomolar or micromolar concentration.

9. A pharmaceutical composition comprising an oligonucleotide according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, excipient, dilutant, stimulant such as an adjuvant, or a combination thereof.

10. The pharmaceutical composition according to claim 9, further comprising a therapeutically active agent.

11. The pharmaceutical composition of claim 9 or 10, or the oligonucleotide according to any one of claims 1 to 8 further inhibiting the activity of a receptor such as a growth receptor selected from the group consisting of TGF-beta receptor I (TβRI), TGF-beta receptor II (TβRII), VEGF, HGF, PDGF and SEMA3 (Plexin), or a combination thereof, or further inhibiting the activity of a signal transduction factor such as p38MAPK, ERK1, ERK2, PI3K, Akt, NF-κB, pSMAD2, pSMAD3, Src, Pyk2, FAK, p-p130Cas, or a combination thereof.

12. The pharmaceutical composition of any one of claims 9 to 11 or the oligonucleotide according to any one of claims 1 to 8 or 11 inhibiting the immigration of a Treg cell into a tumor.

13. The pharmaceutical composition of any one of claims 9 to 12, or the antisense oligonucleotide according to any one of claims 1 to 8, 11 or 12 for use in preventing and/or treating cancer, an ophthalmic disease, an autoimmune disorder and/or an immune disorder.

14. The pharmaceutical composition or the antisense oligonucleotide for use according to claim 13, wherein the ophthalmic disease is an angiogenic eye disease such as age related macular disease (AMD), diabetic retinopathy (DME), retinopathy of prematurity (Retinopathia praematurorum) or corneal neovascularization.

15. The pharmaceutical composition or the antisense oligonucleotide for use according to claim 13, wherein the cancer is bladder carcinoma, breast cancer, colorectal carcinoma, lung cancer, malignant melanoma, mesothelioma, lymphoma, skin cancer, bone cancer, prostate cancer, hepatocarcinoma, brain cancer, cancer of the larynx, liver, gall bladder, pancreas, testicular, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, neuroblastoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, liposarcoma, leukemia, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, meningioma, acute and chronic lymphocytic and granulocytic tumors, acute and chronic myeloid leukemia, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, intestinal ganglioneuromas, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, polycythaemia vera, adenocarcinoma, anaplastic astrocytoma, glioblastoma multiforma, leukemia, or epidermoid carcinoma.

16. The pharmaceutical composition or the antisense oligonucleotide for use according to any one of claims 13 to 15, wherein the oligonucleotide or the composition is administrable locally or systemically.