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WO2004063375A1 - Optimisation d'arnsi par arni antisens - Google Patents

Optimisation d'arnsi par arni antisens Download PDF

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Publication number
WO2004063375A1
WO2004063375A1 PCT/NO2004/000007 NO2004000007W WO2004063375A1 WO 2004063375 A1 WO2004063375 A1 WO 2004063375A1 NO 2004000007 W NO2004000007 W NO 2004000007W WO 2004063375 A1 WO2004063375 A1 WO 2004063375A1
Authority
WO
WIPO (PCT)
Prior art keywords
sirna
rnai antisense
molecules
rnai
nucleic acid
Prior art date
Application number
PCT/NO2004/000007
Other languages
English (en)
Inventor
Hans Prydz
Mohammed Amarzguioui
Torgeir Holen
Original Assignee
Hans Prydz
Mohammed Amarzguioui
Torgeir Holen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from NO20030206A external-priority patent/NO20030206D0/no
Application filed by Hans Prydz, Mohammed Amarzguioui, Torgeir Holen filed Critical Hans Prydz
Publication of WO2004063375A1 publication Critical patent/WO2004063375A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/10—Applications; Uses in screening processes
    • C12N2320/11—Applications; Uses in screening processes for the determination of target sites, i.e. of active nucleic acids

Definitions

  • RNA sequence-specific mediators of RNA interference regards RNA sequence-specific mediators of RNA interference and relates to isolated RNA molecules (double stranded; single stranded) of from about 21 -23 nucleotides in general.
  • WO 01/75164 also relates inter alia to a method of producing said RNA molecules, e.g. by using the Drosophila in vitro system, by chemical synthesis or recombinant techniques.
  • WO 02/44321 disclose inter alia isolated double-stranded RNA molecule of 19-25 nucleotides capable of target-specific nucleic acid modifications, a method for processing said RNA molecules and the use thereof.
  • siRNA modifications would be affected by siRNA modifications, chemical or mutational, in different ways, and generally in a deleterious way, as shown in the exemplary material. Therefore, there is a considerable need for a method to efficiently identify optimal siRNA molecules, which may be chemical modified or not, to be able to develop useful pharmaceutical agents to modulate the expression of a target gene.
  • EP 0 756 634 Bl disclose a method for the screening of a genetic sequence which is capable of inhibiting, reducing, altering or otherwise modulate the expression of a target nucleotide sequence, e.g. the screening for useful antisense, sense or ribozyme constructs or other nucleic sequences. More specifically, the method disclosed in EP 0 756 634 Bl makes use of & pombe to evaluate the effect of the introduction of the molecule to be tested on the expression of a target gene in S. pombe.
  • alkylation such as methylation
  • 3' or 5' end modifications such as fluorescent labels, non-standard nucleotides, lipophilic linker molecules or peptides
  • modification or exchange of the phosphodiester bond e.g. with phosporothioates, methylphosphonates, or polyamide.
  • RNAi antisense could also be expressed endogenouslyfrom appropriate vectors, preferably of viral origin and from RNA polymerase III promoters.
  • appropriate vectors preferably of viral origin and from RNA polymerase III promoters.
  • primer extension analysis which identifies the most prominent cleavage positions within the target mRNA. From the known sequence of target mRNA, the sequence of RNAi antisense causing the most prominent cleavage events can be inferred.
  • RNAi antisense has target position dependence
  • a comparison between RNAi antisense and siRNA can, of course, not conclusively prove a shared RNAi pathway, but major deviations between the two could very well decisively falsify our hypothesis of a shared RNAi pathway.
  • the efficacies of antisense RNAs targeting sites on TF mRNA coding region from the start-codon (as-77) to the stop- codon (as-929) were evaluated in our quantitative Northern assay (Fig. IB).
  • RNAi antisense reaches maximum activity faster than siRNA
  • RNA interference is mediated by 21 and 22 nt RNAs. Genes Dev., 15, 188-200.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé d'identification de séquences efficaces d'ARNsi pouvant être utilisées pour modifier l'expression d'une séquence de gènes cible. De manière spécifique, cette invention concerne un procédé d'identification de sites de ciblage d'ARNsi optimal à l'aide d'ARNi antisens. En outre, ladite invention concerne des molécules d'ARNsi identifiées par le présent procédé de criblage ainsi que des préparations pharmaceutiques contenant lesdites molécules d'ARNsi.
PCT/NO2004/000007 2003-01-15 2004-01-14 Optimisation d'arnsi par arni antisens WO2004063375A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US44003603P 2003-01-15 2003-01-15
NO20030206A NO20030206D0 (no) 2003-01-15 2003-01-15 Screening metode
US60/440,036 2003-01-15
NO20030206 2003-01-15

Publications (1)

Publication Number Publication Date
WO2004063375A1 true WO2004063375A1 (fr) 2004-07-29

Family

ID=32716487

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NO2004/000007 WO2004063375A1 (fr) 2003-01-15 2004-01-14 Optimisation d'arnsi par arni antisens

Country Status (1)

Country Link
WO (1) WO2004063375A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459547B2 (en) 2003-06-02 2008-12-02 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US8304530B2 (en) 2003-06-02 2012-11-06 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US8309704B2 (en) 2003-06-02 2012-11-13 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi
JP2012223202A (ja) * 2004-12-22 2012-11-15 Alnylam Pharmaceuticals Inc 遺伝子サイレンシングに有用なｈｂｖおよびｈｃｖ保存配列
US8329463B2 (en) 2000-12-01 2012-12-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8394628B2 (en) 2000-03-30 2013-03-12 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US8729036B2 (en) 2002-08-07 2014-05-20 University Of Massachusetts Compositions for RNA interference and methods of use thereof
US9879253B2 (en) 2003-12-22 2018-01-30 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended siRNA
US10392619B2 (en) 2009-10-12 2019-08-27 Larry J. Smith Methods and compositions for modulating gene expression using oligonucleotide based drugs administered in vivo or in vitro
US10513703B2 (en) 2014-11-10 2019-12-24 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) iRNA compositions and methods of use thereof
US11324820B2 (en) 2017-04-18 2022-05-10 Alnylam Pharmaceuticals, Inc. Methods for the treatment of subjects having a hepatitis b virus (HBV) infection
US11492623B2 (en) 2018-08-13 2022-11-08 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) dsRNA agent compositions and methods of use thereof
US11926817B2 (en) 2019-08-09 2024-03-12 Nutcracker Therapeutics, Inc. Microfluidic apparatus and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5525468A (en) * 1992-05-14 1996-06-11 Ribozyme Pharmaceuticals, Inc. Assay for Ribozyme target site
WO2002090590A1 (fr) * 1992-09-29 2002-11-14 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de sous unites de l'interleukine 12 p35
WO2003100093A2 (fr) * 2002-05-28 2003-12-04 Isis Innovation Ltd. Procede de selection de cibles pour silençage genique par interference d'arn

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5525468A (en) * 1992-05-14 1996-06-11 Ribozyme Pharmaceuticals, Inc. Assay for Ribozyme target site
WO2002090590A1 (fr) * 1992-09-29 2002-11-14 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de sous unites de l'interleukine 12 p35
WO2003100093A2 (fr) * 2002-05-28 2003-12-04 Isis Innovation Ltd. Procede de selection de cibles pour silençage genique par interference d'arn

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AMARZGUIOUI M ET AL: "Tolerance for mutations and chemical modifications in a siRNA", NUCLEIC ACIDS RESEARCH, vol. 31, no. 2, 15 January 2003 (2003-01-15), pages 589 - 595, XP002270887, ISSN: 0305-1048 *
ELBASHIR SAYDA M ET AL: "RNA interference is mediated by 21- and 22-nucleotide RNAs", GENES AND DEVELOPMENT, vol. 15, no. 2, 15 January 2001 (2001-01-15), pages 188 - 200, XP002204651, ISSN: 0890-9369 *
HOLEN T ET AL: "Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor", NUCLEIC ACIDS RESEARCH, vol. 30, no. 8, 15 April 2002 (2002-04-15), pages 1757 - 1766, XP002232890, ISSN: 0305-1048 *
HOLEN TORGEIR ET AL: "Similar behaviour of single-strand and double-strand siRNAs suggests they act through a common RNAi pathway.", NUCLEIC ACIDS RESEARCH, vol. 31, no. 9, 1 May 2003 (2003-05-01), pages 2401 - 2407, XP002283906, ISSN: 0305-1048 *
SCHWARZ D S ET AL: "EVIDENCE THAT SIRNAS FUNCTION AS GUIDES, NOT PRIMERS, IN THE DROSOPHILA AND HUMAN RNAI PATHWAYS", MOLECULAR CELL, vol. 10, no. 3, September 2002 (2002-09-01), pages 537 - 548, XP009019083, ISSN: 1097-2765 *
SOHAIL M ET AL: "OLIGONUCLEOTIDE SCANNING ARRAYS: APPLICATION TO HIGH-THROUGHPUT SCREENING FOR EFFECTIVE ANTISENSE REAGENTS AND THE STUDY OF NUCLEIC ACID INTERACTIONS", ADVANCES IN BIOCHEMICAL ENGINEERING, BIOTECHNOLOGY, SPRINGER, BERLIN, DE, vol. 77, 2002, pages 43 - 56, XP008026711, ISSN: 0724-6145 *
VICKERS TIMOTHY A ET AL: "Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents: A comparative analysis.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 9, 28 February 2003 (2003-02-28), pages 7108 - 7118, XP002283905, ISSN: 0021-9258 *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8394628B2 (en) 2000-03-30 2013-03-12 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US10472625B2 (en) 2000-03-30 2019-11-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA sequence-specific mediators of RNA interference
US9193753B2 (en) 2000-03-30 2015-11-24 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US9012621B2 (en) 2000-03-30 2015-04-21 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA sequence-specific mediators of RNA interference
US9012138B2 (en) 2000-03-30 2015-04-21 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA sequence-specific mediators of RNA interference
US8790922B2 (en) 2000-03-30 2014-07-29 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA sequence-specific mediators of RNA interference
US8742092B2 (en) 2000-03-30 2014-06-03 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US8632997B2 (en) 2000-03-30 2014-01-21 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US8552171B2 (en) 2000-03-30 2013-10-08 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US8420391B2 (en) 2000-03-30 2013-04-16 University Of Massachusetts RNA sequence-specific mediators of RNA interference
US8895721B2 (en) 2000-12-01 2014-11-25 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8372968B2 (en) 2000-12-01 2013-02-12 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8362231B2 (en) 2000-12-01 2013-01-29 Max-Planck-Gesellschaft zur Föderung der Wissenschaften E.V. RNA interference mediating small RNA molecules
US8445237B2 (en) 2000-12-01 2013-05-21 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8329463B2 (en) 2000-12-01 2012-12-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US10633656B2 (en) 2000-12-01 2020-04-28 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. RNA interference mediating small RNA molecules
US8993745B2 (en) 2000-12-01 2015-03-31 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8895718B2 (en) 2000-12-01 2014-11-25 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8765930B2 (en) 2000-12-01 2014-07-01 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8778902B2 (en) 2000-12-01 2014-07-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8933044B2 (en) 2000-12-01 2015-01-13 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8796016B2 (en) 2000-12-01 2014-08-05 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US8853384B2 (en) 2000-12-01 2014-10-07 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
US9611472B2 (en) 2002-08-07 2017-04-04 University Of Massachusetts Compositions for RNA interference and methods of use thereof
US8729036B2 (en) 2002-08-07 2014-05-20 University Of Massachusetts Compositions for RNA interference and methods of use thereof
US8304530B2 (en) 2003-06-02 2012-11-06 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US7732593B2 (en) 2003-06-02 2010-06-08 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US7459547B2 (en) 2003-06-02 2008-12-02 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US8309704B2 (en) 2003-06-02 2012-11-13 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi
US8309705B2 (en) 2003-06-02 2012-11-13 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US9121018B2 (en) 2003-06-02 2015-09-01 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US7772203B2 (en) 2003-06-02 2010-08-10 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US10604754B2 (en) 2003-06-02 2020-03-31 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US11459562B2 (en) 2003-06-02 2022-10-04 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US10364429B2 (en) 2003-06-02 2019-07-30 University Of Massachusetts Methods and compositions for controlling efficacy of RNA silencing
US8329892B2 (en) 2003-06-02 2012-12-11 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNA silencing
US10385339B2 (en) 2003-12-22 2019-08-20 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended siRNA
US9879253B2 (en) 2003-12-22 2018-01-30 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended siRNA
JP2015003913A (ja) * 2004-12-22 2015-01-08 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 遺伝子サイレンシングに有用なｈｂｖおよびｈｃｖ保存配列
JP2012223202A (ja) * 2004-12-22 2012-11-15 Alnylam Pharmaceuticals Inc 遺伝子サイレンシングに有用なｈｂｖおよびｈｃｖ保存配列
US10392619B2 (en) 2009-10-12 2019-08-27 Larry J. Smith Methods and compositions for modulating gene expression using oligonucleotide based drugs administered in vivo or in vitro
US11359201B2 (en) 2009-10-12 2022-06-14 Larry J. Smith Methods and compositions for modulating gene expression using oligonucleotide based drugs administered in vivo or in vitro
US11060091B2 (en) 2014-11-10 2021-07-13 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) iRNA compositions and methods of use thereof
US10513703B2 (en) 2014-11-10 2019-12-24 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) iRNA compositions and methods of use thereof
US11324820B2 (en) 2017-04-18 2022-05-10 Alnylam Pharmaceuticals, Inc. Methods for the treatment of subjects having a hepatitis b virus (HBV) infection
US11492623B2 (en) 2018-08-13 2022-11-08 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) dsRNA agent compositions and methods of use thereof
US12173289B2 (en) 2018-08-13 2024-12-24 Alnylam Pharmaceuticals, Inc. Hepatitis B virus (HBV) dsRNA agent compositions and methods of use thereof
US11926817B2 (en) 2019-08-09 2024-03-12 Nutcracker Therapeutics, Inc. Microfluidic apparatus and methods of use thereof

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