Journal of Pre-Clinical and Clinical Research 2024, Vol 18, No 4, 303-311

ORIGINAL ARTICLE www.jpccr.eu

New horizons in understanding and treating

Pompe disease – diagnosis and therapy.
A literature review
Weronika Zegardło1,A-D , Karolina Jankowiak1,B-D , Bartłomiej Kwiatkowski1,B,D ,
Zuzanna Kabała1,B,D , Maria Nowakowska1,B,D , Julia Osipowska1,B,D ,
Magdalena Chrościńska-Krawczyk2,F , Aleksandra Witas1,E
1
Student’s Scientific Association of Paediatric Neurology, Medical University, Lublin, Poland
2
Department of Children’s Neurology, University Children’s Hospital, Lublin, Poland
A – Research concept and design, B – Collection and/or assembly of data, C – Data analysis and interpretation,
D – Writing the article, E – Critical revision of the article, F – Final approval of the article
Zegardło W, Jankowiak K, Kwiatkowski B, Kabała Z, Nowakowska M, Osipowska J, Chrościńska-Krawczyk M, Witas A. New horizons
in understanding and treating Pompe disease – Diagnosis and Therapy. A literature review. J Pre-Clin Clin Res. 2024; 18(4): 303–311.
doi: 10.26444/jpccr/193653

Abstract
Introduction and Objective. Pompe disease (PD) is a genetic and metabolic disorder caused by a mutation in the GAA
gene, which leads to a deficiency of acid alpha-glucosidase and glycogen deposition in lysosomes. The aim of the study is
to review the genetic mechanisms, diagnostic approaches, and potential treatments for PD to improve our understanding
and develop effective interventions. 
Review Methods. The review examines articles from databases like PubMed, Google Scholar, Clinicaltrials.gov, and NCBI.
Meta-analyses, randomized controlled trials, and research articles on PD, diagnosis and therapy were included after initial
analysis. More than 95% of the articles are less than eight-years-old.
Brief description of the state of knowledge. Pompe disease has been a known clinical condition for almost a century,
presenting challenges for diagnosis and treatment. Diagnosis can be difficult due to its similarity to other neuromuscular
disorders. However, confirmation of the diagnosis can be achieved through enzymology and molecular genetic testing. The
current treatment for PD is enzyme replacement therapy using recombinant human alpha-glucosidase. Ongoing research
aims to develop improved or new enzymes, as well as other treatments, such as gene therapy and substrate reduction
strategies. Early diagnosis and treatment are crucial. Neonatal screening is recommended. 
Summary. Despite advancements in understanding the pathogenesis of PD, the genetic mechanisms underlying its
phenotypic variations remain unclear. Reporting cases to databases is crucial for unravelling the molecular basis of symptoms
and improving patient outcomes. New therapeutic approaches, such as modified enzyme replacement therapies and gene
editing, are essential for overcoming current limitations and improving treatment efficacy in PD.
Key words
Pompe disease, Glycogen Storage Disease Type II, genetic therapy, enzyme replacement therapy

INTRODUCTION (NBS) in different countries have revealed much higher

figures, ranging from 1:4,447 – 1:37,094 [5,6].
Pompe disease (PD), also known as glycogenosis type II or In recent decades, there have been significant advances
acidic maltase deficiency, is a rare genetic and metabolic in the understanding of the pathophysiology of PD and the
disease caused by an autosomal recessive mutation in the development of therapeutic strategies. The most significant
GAA gene, which encodes acid alpha-glucosidase (GAA). advance in the treatment of the disease has been the
This results in a deficiency or absence of GAA, leading to introduction of enzyme replacement therapy (ERT) using
glycogen deposition in lysosomes throughout the human recombinant GAA (rhGAA). While this therapy is not
body [1,2]. PD was first identified in 1932 by pathologist capable of completely halting progression of the disease, it
Joannes C. Pompe, who described the symptoms of idiopathic markedly enhances the quality and length of life of patients.
cardiac hypertrophy in a seven-month-old female infant. In Nevertheless, modifications of ERT and attempts to utilize
1963, Henri-Gery Hers discovered GAA and established it gene therapies that could improve treatment outcomes are
as the cause of PD [1,3]. still being developed. In order to achieve effective treatment
PD has two basic forms: infantile-onset (IOPD), which of PD, it is important to be able to rapidly identify patients
is characterised by GAA activity below 1%, and late-onset who are experiencing symptoms of the disease. This can
(LOPD), which has a less severe course of the disease [2,4]. be achieved through the use of newborn screening (NBS)
The global prevalence of PD was previously estimated at 1 in management.
40,000 live births; however, newborn screening programmes The aim of the study is to review the current understanding
of the genetic mechanisms underlying PD, existing diagnostic
 Address for correspondence: Weronika Zegardło, Student’s Scientific Association
of Paediatric Neurology, Medical University of Lublin, Poland approaches, and potential therapeutic interventions,
E-mail: weronikazegardlo@o2.pl including novel experimental treatments. A comprehensive
Received: 23.05.2024; accepted: 24.09.2024; first published: 11.10.2024 analysis of these aspects is essential to improve our
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understanding of PD, and to advance the development of respiratory failure represent a significant cause of mortality.
effective treatments. [5,12,13]. Additionally, cardiovascular abnormalities,
including cardiac arrhythmias and arterial aneurysms,
including those in the arteries of the central nervous system
MATERIALS AND METHOD (CNS), have been observed in patients with LOPD [12,13].
However, myocardial hypertrophy, a characteristic of IOPD,
The review considers articles published in databases such is rarely seen in patients with LOPD. [5,12]
as PubMed, Google Scholar, Clinicaltrials.gov, and NCBI Gastrointestinal symptoms, including dysphagia, diarrhea,
databases. English language publications were included using faecal incontinence, abdominal discomfort, malabsorption
search terms such as ‘Pompe disease’, ‘etiology’, ‘diagnosis’, and constipation, are prevalent and markedly impact on the
‘enzyme replacement therapy’ and ‘gene therapy’. After a quality of life of patients, and the prevalence of psychological
preliminary analysis, meta-analyses, randomized controlled disorders [12,13]. Psychological issues, including a reduction
trials, review and research articles of PD, diagnosis, and in social activity, anxiety and depression, are further
therapy of PD, were included. Over 95% of the articles are exacerbated by the presence of chronic pain, fatigue, and
less than eight-years-old. incontinence [5,12]

Clinical phenotypes – Infantile onset of Pompe disease Molecular genetic of PD. Pompe disease is an autosomal
(IOPD). IOPD is typically diagnosed shortly after birth recessive disorder caused by mutations in the GAA gene
or in the first few months of life [1]. If left untreated, the which encodes the enzyme alpha-1,4-glycosidase (GAA).
disease progresses rapidly, and patients usually become The primary function of the GAA enzyme is to catalyse the
dependent on respiratory support at 4.7 months of age hydrolysis of the alpha-1,4-glucosidic chains of glycogen
due to the involvement of the diaphragm and respiratory in the acidic pH environment of lysosomes. Consequently,
muscles. [3,7]. The initial symptoms of the condition include a decrease in GAA activity leads to the accumulation of
slowed movement with decreased muscle tone (52–96% of glycogen in the lysosome [1].
patients), hepatosplenomegaly (29–90% of patients), and The GAA gene is located on the long arm of chromosome
macroglossia (29–62% of patients) [1,9]. IOPD is distinguished 17 (17q25.3) and is approximately 28 kb in length. It consists
by cardiovascular involvement, manifesting as hypertrophic of 20 exons, including a non-coding first exon containing a
cardiomyopathy in approximately 90% of cases and left 5’-untranslated sequence [1,2]. The GAA enzyme precursor
ventricular outflow tract closure. This results in a reduced is transported to the endoplasmic reticulum (ER) by
ejection fraction and heart failure, which represents a amino-terminal peptide sequences. Here, it undergoes
significant cause of mortality in IOPD. [8–10]. Furthermore, N-glycosylation before being transported to the Golgi
cardiac arrhythmias, including supraventricular or ventricular complex. High-mannose oligosaccharide side chains are
tachycardia or premature beats, may be present [4,10]. further modified to deliver GAA to lysosomes via the
The ability to attain certain motor milestones, such mannose-6-phosphate receptor (M6PR) [2]. The final
as sitting or standing, may be delayed or absent due to processing produces a 70 kDa mature form of the enzyme.
a congested muscular system. Gastrointestinal muscle The GAA gene is the only gene associated with PD. The
weakness is linked to dysphagia, gastroparesis, and chronic ‘Pompe disease GAA variant database’ [14] provides a
constipation. Furthermore, hyporeflexia or areflexia, droopy comprehensive list of reported GAA variants, accompanied
eyelids, scoliosis, and winged scapula have been observed [8]. by a severity classification system proposed by Kross
Abnormal lung ventilation can increase the risk of recurrent et al. [14,15]. This system comprises six classes (A-F). The
upper respiratory tract infections and pneumonia, and may distribution of each class is shown in Figure 1, illustrating
contribute to sleep disturbances, particularly during REM the frequency of their occurrence. In addition, the database
sleep [7,8] contains information on cross-reactive immunological
In the brain, there appears to be a reduction in myelin in material (CRIM) status [14,16]. CRIM-negative status has
the periventricular white matter, which can lead to seizures, been associated with poorer prognosis and response to
encephalopathy and future cognitive impairment [11]. ERT [16].
Hearing impairment, assessed by behavioural audiometry
and evoked potentials, has been documented in some
individuals [3,8].

Late-onset Pompe disease (LOPD). LOPD typically presents

symptoms from infancy to adulthood, with the severity and
age of onset dependent on the GAA variant and the degree
of enzyme activity [1, 5]. The disease is characterized by the
hallmark sign of progressive symmetric proximal myopathy,
but the pattern of muscle involvement is variable and may
be regional. The lower extremities and spinal muscles are
usually affected earlier than other regions of the body. As the
disease progresses, motor weakness leads to the development
of scoliosis and lumbar hyperlordosis. In some cases, patients
may develop stiff spine syndrome (RSS) [12,13].
Respiratory muscles are frequently affected in LOPD, and Figure 1. Frequency of a particular class of GAA variants reported in the Pompe
associated complications such as recurrent infections and disease GAA variant database [14]
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The current database documents a total of 911 variants of the Chinese and Taiwanese cohort were c.1935C>A and
mutations – 232 intronic and 678 exonic [14], two of which c.2238G>C, while c.546G>T was over-represented in Japanese
involve the deletion of the entire GAA gene. All types of PD patients [17]. The c.2560C>T mutation has affected many
mutations have been recorded, covering disorders related to African or African-American patients with IOPD [16].
protein structure formation. Missense mutations are the most The relationship between the level of GAA activity and
prevalent, followed by small deletions [2]. Figure 2 shows the phenotype in PD is complex and does not solely indicate the
distribution of GAA variants based on their severity class and severity of the disease. Patients with GAA activity levels below
their localization in exonic and intronic regions. 1% usually present with a severe form of IOPD. Conversely, the
The spectrum of mutations is heterogeneous and genetic most common severity class in patients with LOPD is class D,
variants often occur only in small populations, except for the with GAA activity levels between 5% – 30%. However, patients
splicing mutation c.-32–13T>G, which is the most prevalent with IOPD with GAA variants indicating mild potentially
in the Caucasian population [1,16]. This intronic mutation class, have also been reported in the database [14,15]
causes a splicing defect that results in the skipping of exon Due to the lack of strict genotype/phenotype correlations
2, reducing the level of synthesis of the correct enzyme. In and the variable response to treatment, researchers are
homozygotes with this mutation, a variable level of residual searching for genes that modify GAA expression. Previous
GAA activity and a delay in the manifestation of phenotypes studies have suggested that the insertion/deletion (I/D)
have been observed [16]. The most common mutations in polymorphism of the ACE gene, which encodes the

Figure 2. GAA genetic variants distribution into exonic and intronic localization in all reported in database (a) and in individual severity classes (b) [14]
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angiotensin I-converting enzyme (ACE), may be a modifier for monitoring disease progression and plays an important
of disease onset and/or response to enzyme replacement role in clinical trials and treatment follow-up. The technique
therapy (ERT). However, the association with ACE I/D is used to evaluate muscle fat infiltration and atrophy in PD is
polymorphism, as well as with other possible modifier genes, quantitative muscle MRI (qMRI). This non-invasive measure
remains controversial [18]. can visualize and quantify muscle degeneration [25]. Unlike
conventional magnetic resonance imaging (MRI), qMRI can
Diagnostic tools. Rare diseases, such as PD, can present detect microstructural processes of tissue remodelling and
with symptoms that are difficult to recognize and can only damage, even in tissue that appears normal on conventional
be diagnosed through genetic testing. Unfortunately, the MRI imaging. [25,26].
diagnostic process can take months, and in some cases this Recent studies indicate that microRNAs may serve as
delay can lead to death before the cause is even known [1,3]. a biochemical marker for PD. These non-coding RNA
Similarly, LOPD patients may experience a slower onset of molecules play a crucial role in post-transcriptional gene
symptoms, which can prolong the diagnostic journey for expression regulation [27]. One specific microRN – miR-
years [3,5]. 133a – is expressed in both skeletal and cardiac muscle.
The primary method of diagnosing PD is to detect the Analysis of plasma samples from PD patients showed
absence of GAA activity in lysosomes and to identify significantly higher levels of miR-133a than in controls.
mutations in the gene encoding the enzyme [1,19]. However, According to the study, miR-113a levels were found to be
one of the challenges of enzymatic diagnosis is the presence higher in patients with IOPD than in those with LOPD [28].
of pseudo-deficiencies, such as GAA variants, which do not For patients with IOPD, early diagnosis through ERT is
cause PD but reduce the activity of the enzyme [1]. GAA crucial, and the diagnostic process needs to be accelerated.
activity can be measured in leukocytes, dried blood spots One solution to this problem, at least in part, is NBS. NBS
(DBS) or fibroblasts from muscle or skin biopsies [20,21]. For was first introduced in Taiwan in 2005, and has since been
efficient screening and diagnosis, it is highly advantageous implemented as a pilot or regular programme in several
to use DBS or leukocytes as they are easy to obtain. The countries, including Japan, some regions of Italy, Australia,
guidelines for diagnosing PD recommend a combination of several states in the USA, Austria, Hungary, Mexico, and
enzymatic assays confirmed by gene sequencing as the gold Brazil [1,21]. The NBS method measures GAA activity in
standard [1,19,20]. DBS using techniques such as fluorometry, tandem mass
Muscle biopsy is a quite specific test for PD, and the spectrometry, or digital microfluidic fluorometry [20,21].
diagnosis of PD may also be supported by a muscle biopsy. NBS is especially crucial in IOPD patients, as improved
Histological examination may reveal certain features, overall survival and mechanical ventilation-free survival in
such as the presence of vacuoles filled with PAS-positive previously treated patients. Chien et al. analyzed the results
material – glycogen and autophagic deposits containing of three cohorts which showed that patients detected with
large autofluorescent inclusions composed of lipofuscin, NBS had 100% overall and ventilator-free survival at 150
an indigestible intralysosomal material typically associated months. In comparison, later-diagnosed and ERT-treated
with the aging process [5,22]. Muscle biopsy can improve the patients had an overall survival of approximately 50%, and
understanding of response to treatment; for example, it has ventilator-free survival of approximately 20% at 150 months
allowed the description of a previously unreported pathology [20]. In countries with experience of NBS and improved
that is ERT-resistant in cases of LOPD [5,22]. diagnostic methods, the time from diagnosis to initiation
A useful diagnostic tool for the early identification of of ERT has been significantly reduced, even up to one day
people with LOPD is spirometry, which is highly effective for after diagnosis [20,21].
detecting the signs of respiratory impairment commonly seen In LOPD patients, the variability of phenotypes is high and
in LOPD. Forced vital capacity (FVC) should be measured the timing of symptom onset cannot be predicted at the time
in both the seated and supine positions. A decrease in FVC of diagnosis. Nevertheless, early detection by NBS allows close
of more than 10% when changing position from sitting to monitoring of patients with LOPD, increasing the likelihood
lying down indicates diaphragmatic weakness, which may of initiating ERT at the onset of symptoms [6,20]. Although
precede proximal myopathy and may qualify a patient for NBS has been shown to provide many benefits, it has also
ERT before full-blown disease symptoms, and may also be been reported to cause psychological problems for families of
used to assess response to treatment [19, 23]. LOPD patients. Many families reported feeling uninformed
Elevated levels of creatine kinase (CK), transaminases at the time of diagnosis and experiencing increased anxiety
(alanine transaminase (ALT) and aspartate transaminase and hypervigilance to symptoms, highlighting the need for
(AST) and lactate dehydrogenase (LDH) are sensitive but standardized psychological care [6,21].
non-specific markers for LOPD [1]. CK levels are typically An important limitation of NBS is that it cannot detect
elevated in patients with LOPE, ranging from 1.5 – 15 times GAA deficiency, which means low enzyme activity in tests
the upper limit of normal [23]. Persistent hyperCKemia but no clinical symptoms of the disease. This relationship may
accompanied by respiratory insufficiency and proximal account for the likely overestimation of PD incidence rates.
muscle weakness should be further investigated for LOPD Consequently, there is also a risk of over-treatment, which
[20,24]. An increase in urinary glucose tetrasaccharide may not be beneficial to patients and may be costly in terms
(Glc4) does not differentiate PD from other glycogen storage of time and resource [21]. It is crucial to highlight that NBS
disorders; however, it may support the diagnosis when clinical is not a diagnostic tool, therefore any positive result must
findings are consistent and can be useful in monitoring be further verified as false positive results may occur.[19,21]
treatment outcomes in clinical trials [1].
Another tool that can be used for monitoring the changes Treatment approaches – current therapeutic standards. ERT
in PD is qMRI of the muscle, which is particularly valuable is the current standard treatment for PD [1,4]. This treatment
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involves intravenous infusions of human recombinant alpha- respiratory support and respiratory muscle training [1,4,34],
glucosidase (rhGAA), which is transported to the lysosome with recent guidelines suggesting the inclusion of exercise
via M6PR, enabling patients with LSD to metabolize glycogen under professional supervision [34]. Other treatments, such
properly [1,29]. The search for a cure for PD has a long history, as an oral/nasogastric/gastrostomy tube, hearing aids and
dating back to the 1960s with the discovery of GAA [3,5]. speech therapy should be considered [34].
Trials in patients were conducted using enzymes from Although the introduction of alglucusidase alfa offers hope
human placenta and Aspergillus Niger, rabbit milk, and for changing the prognosis for all people with PD, it is not
Chinese hamster ovary cells [19 – 31]. As a result, in 2006, a panacea. Heterogeneous responses have been observed in
alglucosidase alfa became the first rhGAA to be approved all forms of PD, and the health of most patients improves
for both IOPD and LOPD [30,32]. to some degree. However, studies show that IOPD patients
Although ERT is generally considered safe, it can cause lose motor milestones over time and about 50% of patients
adverse effects which can be divided into two main groups: experience a decline in respiratory function [10,30]. Although
infusion-associated reactions (IARs) and the development cardiomyopathy is reversible in most patients within months
of anti-rhGAA IgG antibody titers [30,33,34]. The most to a year of treatment, other cardiac dysfunctions, such as
commonly reported IARs in patients receiving ERT are arrhythmias, may occur. [10,31]. After an initial improvement
typically mild-to-moderate in severity and do not usually in respiratory and motor function, most LOPD patients
interfere with continued administration of ERT [19,30]. experience a regression or plateau [4,19].
Premedication with antihistamines, corticosteroids and
antipyretics or desensitization may be given in the event of Novel and experimental therapy methods. In the light of
IARs [1,19]. the unsatisfactory results of current treatments, particularly
A more significant concern is the development of anti- in improving respiratory and neurological function, there
drug antibodies (ADAs), which can either inhibit the is a need for new therapeutic options [30,37]. Promising
activity of rhGAA or reduce its uptake by cells [34,35]. developments in this area include molecular modifications
In particular, IOPD patients with negative CRIM status of the rhGAA and gene-modifying applications, such as
are more susceptible to deterioration in ERT efficacy due adeno-associated viral (AAV) gene therapy and lentiviral
to the development of ADAs. CRIM status determines a (LV) vectors for ex vivo haematopoietic stem cell (HSPC) gene
patient’s ability to endogenously synthesis GAA, with GAA therapy. Table 1 presents an overview of clinical trials for gene
produced by CRIM-positive patients being non-functional therapy, while Table 2 displays current clinical trials for ERT.
but inducing higher immune tolerance to rhGAA [35]. To
prevent the development of ADAs and reduce their amount, a ERT modifications. One possible strategy to improve the
prophylactic immune tolerance induction (ITI) protocol can efficacy of ERT is to increase the binding of rhGAA to the
be administered, which includes methotrexate, rituximab, cation-independent MP6R (CI-M6PR) [4,39]. This can be
intravenous immunoglobulin, and sometimes bortezomib achieved by conjugating oligosaccharides involving bis-
[19, 35]. It has been shown that ITI is more effective in mannose-6-phosphate (bis-M6P), which is then attached
ERT-naive patients and with a shorter duration of therapy. to the rhGAA. This methodology has been employed to
Therefore, it is crucial to determine a patient’s CRIM status develop second-generation rhGAA therapeutics, including
by Western blot analysis before starting ERT. Unfortunately, Avalglucosidase-alpha (Nexviadyme), which was approved
studies have shown that CRIM-positive PD patients can also by the Food and Drug Administration (FDA) in 2021 for
develop ADAs [33]. the treatment of LOPD in patients aged one year and older
Treatment guidelines suggest ERT at a dose of 20 mg/kg [3,4] following positive results from a recent randomised,
every two weeks [30,32,33] as soon as patients are diagnosed phase 3 trial (COMET) [39]. The recommended dose of
with IOPD [34,37], and at the onset of symptoms in LOPD avalglucosidase alpha is 20 mg/kg body weight administered
with a confirmed diagnosis [19,32]. The standard dose of once every two weeks [5,39]. Currently, there are two ongoing
20 mg/kg every two weeks was established based on the first clinical trials (NCT03019406, NCT04910776) focusing on
pivotal clinical trials, as higher doses of ERT did not prove infants with IOPD. Another potential approach to achieve
to be more effective. However, a multi-centre retrospective this goal is the incorporation of a glycosylation-independent
study of 28 IOPD patients revealed that those who initiated lysosomal targeting (GILT) peptide tag consisting of a
ERT earlier or received higher weekly or fortnightly doses, segment of insulin-like growth factor 2 (IGF2). The aim of this
had a lower risk of motor decline [32,33]. A multi-centre modification is to increase the affinity of rhGAA for the IGF2
observational study was conducted on a cohort of 116 IOPD binding site on the IGF2R/CI-M6PR receptor [37,39]. This
patients. Higher doses were administered to classic IOPD method has been applied to BMN 701, a GILT-tagged rhGAA,
patients and showed that those treated with 40 mg/kg weekly and has been evaluated in open-label study (NCT01230801)
had a higher overall survival rate than those treated with the and a phase 3 switchover study (NCT01435772), both
standard dose. However, the effect on motor function was not involving intravenous infusion in LOPD patients. The results
statistically significant [29]. Although these results suggest of these studies have shown improvements in respiratory
the possibility of dose escalation in routine ERT, more data function and walking endurance [38]
is needed to support this, particularly in the adult cohort of The bioavailability of rhGAA can also be improved by using
LOPD patients [29,36]. small molecule chaperones to enhance the enzymatic activity
ERT is currently the only internationally approved disease- of GAA. Chaperones facilitate the proper folding of the GAA
modifying therapy for PD. However, PD is a multi-systemic protein, allowing it to maintain its catalytic activity and prevent
disease and management should be multidisciplinary [1,4]. premature degradation in the ER [40,41]. Cipaglucosidase
Medical care for PD patients should include appropriate alfa (Pombiliti™), an rhGAA product under development by
immunization [4,10,12], consideration of non-invasive Amicus Therapeutics in Philadelphia, USA, along with the
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Table 1. Overview of clinical trials for gene therapy [38]

NCT number Treatment Status Phase Description

NCT02240407 rAAV9-DES-hGAA completed Phase 1 Randomized, controlled study evaluating the toxicology, biodistribution and potential
activity of re-administration of rAAV9-DES-hGAA injected intramuscularly into the TA.
NCT03533673 AAV2/8-LSPhGAA (ACTUS-101) active Phase 1 Prospective, open-label trial designed to objectively assess the safety and bioactivity of
ACTUS-101 in subjects diagnosed with LOPD
NCT00976352 rAAV1-CMV-GAA completed Phase 1/2 Trial of Diaphragm Delivery of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase
(rAAV1-CMV-GAA) Gene Vector in Pediatric Subjects Aged 2 to < 18 Years with PD
NCT04093349 SPK-3006 (adeno-associated active Phase 1/2 Dose-escalation Study to Evaluate the Safety, Tolerability and Efficacy of a Single Intravenous
viral (AAV) vector) Infusion of SPK-3006 in Adults With LOPD receiving ERT
NCT06178432 CRG003 (BBM-G102, AAV not yet Early A Single-arm, Open-label, Single-dose Study to Evaluate the Safety, Tolerability, and Efficacy
vector) recruiting Phase 1 of CRG003 Injection in the Treatment of LOPD with a long-term follow-up period of 5 years.
NCT05567627 GC301 ( AAV vector) recruiting Not Single Arm, Multicenter, Open and Dose-escalation Clinical Study on Safety, Tolerance, and
Applicable Efficacy of GC301, an AAV-Delivered Gene Transfer Therapy in Patients With IOPD
NCT05793307 Phase 1/2 A Multi-cantered, Single Arm, Open-Label, Study to Evaluate the Safety and Efficacy of
an Adeno-associated Virus Vector Expressing the Human Acid Alpha-glucosidase (GAA)
Transgene Intravenous Injection in Patients With IOPD
NCT04174105 zocaglusagene nuzaparvovec recruiting Phase 1/2 Open-Label, Ascending-Dose Clinical Study to Evaluate the Safety and Preliminary Efficacy of
(AT845, AAV8-Delivered Gene AT845, an AAV8-Delivered Gene Transfer Therapy in Patients With LOPD (FORTIS)
Transfer Therapy)

Table 2. Current clinical trials for ERT [38]

NCT number Treatment Status Phase Description

NCT04676373 Alglucosidase recruiting Phase 4 A Single Arm, Prospective, Open-label, Multi-center Study to Evaluate Efficacy and Safety in Chinese Patients
alfa (Myozyme) With Late Onset Pompe Disease With Alglucosidase Alfa Treatment (APOLLO-LOPD)
NCT05164055 Avalglucosidase Active, not Phase 4 A French Multicenter Open Label Phase 4 Extension Study of Long-term Safety and Efficacy in Patients With
Alfa recruiting Pompe Disease Who Previously Participated in Avalglucosidase Alfa Development Studies in France
NCT03019406 Active, not Phase 2 An Open-label Ascending Dose Cohort Study to Assess the Safety, Pharmacokinetics, and Preliminary
recruiting Efficacy of Avalglucosidase Alfa (NeoGAA) in Patients With IOPD Treated With Alglucosidase Alfa Who
Demonstrate Clinical Decline or Sub-optimal Clinical Response (Mini-COMET)
NCT04910776 recruiting Phase 3 An Open-label, Multinational, Multicenter Study of the Efficacy, Safety, Pharmacokinetics, and
Pharmacodynamics of Avalglucosidase Alfa in Treatment naïve Pediatric Participants with IOPD (Baby-
COMET)
NCT04532047 Aldurazyme recruiting Phase 1 In Utero Enzyme Replacement Therapy (ERT) for Prenatally Diagnosed Lysosomal Storage Disorders (LSDs)
(laronidase) (IUTER) fetal ERT
NCT04138277 Cipaglucosidase active, not Phase 3 A multicenter, open-label extension study of ATB200/AT2221 in adult subjects with LOPD who completed
Alfa/Miglustat recruiting Study ATB200-03
[rhGAA (ATB200)
NCT04808505 recruiting Phase 3 An Open-label Study to Evaluate the Safety, Efficacy, Pharmacokinetics, Pharmacodynamics, and
co-administered
Immunogenicity of Cipaglucosidase Alfa/Miglustat in Both ERT-experienced and ERT-naïve Pediatric
with a chaperone
Subjects With Infantile-onset Pompe Disease Aged 0 to < 18 Years (ROSSELLA)
(AT2221)]
NCT03911505 recruiting Phase 3 An Open-label Study of the Safety, Pharmacokinetics, Efficacy, Pharmacodynamics, and Immunogenicity of
Cipaglucosidase Alfa/Miglustat in Pediatric Subjects Aged 0 to < 18 Years With LOPD
NCT03865836 available An expanded access program (EAP) for eligible participants designed to provide access to ATB200/AT2221.
NCT02675465 active Phase 1/2 An Open-Label, Fixed-Sequence, Ascending-Dose, First-in-Human Study to Assess the Safety, Tolerability,
Pharmacokinetics, Pharmacodynamics, and Efficacy in Adult Subjects With Pompe Disease

small-molecular chaperone miglustat, was granted approval alfa and miglustat demonstrated the potential for clinically
in the European Union (EU) on 27 March 2023, as a two- meaningful improvements in motor and respiratory function,
component long-term ERT for the treatment of adults with while maintaining a comparable safety profile to that of
LOPD [40]. The recommended dosage of cipaglucosidase alglucosidase alfa plus placebo [40, 41].
alfa is 20 mg/kg administered intravenous every two weeks. An attempt has been made to deliver rhGAA to the cell via the
The results of a phase I/II trial (NCT02675465) revealed equilibrative nucleoside transporter 2 (ENT2), independent
that the combination of cipaglucosidase alfa and miglustat of the CI-M6PR, using VAL-1221 (Valerion Therapeutics), a
effectively reduced biomarkers of muscle damage (CK) fusion protein of the lupus anti-DNA monoclonal antibody
and glycogen accumulation (Glc4) in patients with LOPD, 3E10 with rhGAA (NCT02898753). However, a clinical trial
particularly among those who had not received ERT. In was discontinued due to lack of funding [30]. Targeting the
the randomized, phase III PROPEL trial (NCT03729362), transferrin receptor (TfR) has also been explored as a way to
cipaglucosidase alfa plus miglustat did not achieve statistical improve efficacy across the blood-brain barrier (BBB). This is
superiority over alglucosidase alfa plus placebo in terms of achieved by binding rhGAA to an anti-human TfR antibody,
improving the six-minute walk distance (6MWD) in patients allowing transcytosis across the BBB and subsequent delivery
with LOPD. However, the combination of cipaglucosidase to the CNS compartment [37].
Journal of Pre-Clinical and Clinical Research 2024, Vol 18, No 4 309
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Figure 3. a) Overall mechanism of action of rhGAA therapy in the cell: 1. rhGAA binds to CI-M6PR on the cell surface, where it undergoes endocytosis via clathrin-coated
pits. 2. The rhGAA and CI-M6PR complex is transported via the endocytic pathway to the early endosome. 3. Following the disconnection of CI-M6PR in a lowered
pH environment of the late endosome, rhGAA is transported into the lysosome. 4. In an acidic lysosomal environment, glycogen is degraded by the active GAA form
following proteolytic cleavage and N-glycan trimming. b) The general principle of the newly approved rhGAAs for the treatment of PD CI-MPR, cation-independent
mannose-6-phosphate receptor; rhGAA, recombinant human acid alpha-glucosidase; bis-M6P, bis-mannose-6-phosphate [37,39,40,41]

Gene therapy for PD. The Adeno-associated virus (AAV) diaphragm [37]. These trials also confirmed the feasibility of
is a single-stranded DNA virus of the Parvoviridae family, using liver cells to produce recombinant proteins and reduce
characterized by a biphasic life cycle with productive and the immune response to transgenic products. In addition,
latent phases [42]. Successful gene therapy using recombinant studies using a hybrid tandem liver-muscle promoter (LiMP)
AAV vectors has been demonstrated in murine models of and AAV8 and AAV9 serotypes injected into Gaa-/-mice
PD [37]. showed a reduction in anti-GAA antibody production
In a preclinical study,? – delivered the AAV1-CMV-GAA compared to ERT [37,44]. These findings led to the initiation
vector within the diaphragm using a glycerine-based gel and of clinical trials to assess the safety of AAV2/8-LSPhGAA
demonstrated tropism of the AAV1 serotype in the expression (ACTUS-101) in LOPD patients (NCT03533673). Various
of GAA across the diaphragm [37]. An important finding was modifications have been introduced to increase GAA protein
the attenuation of efferent phrenic nerve activity, indicating secretion by transduced liver cells and optimize transgene
retrograde transduction. This method has also been utilized expression, such as the use of a specific human alpha1-
in a clinical trial with IOPD patients, aimed at improving antitrypsin (hAAT) signal peptide, or an N-terminal deletion
respiratory function, compared to baseline (NCT 00976352) fused to a codon-optimized GAA [37]. In a preclinical
[43]. Although satisfaction levels improved during the first study involving non-human primates, the AAV8-hAAT-
180 days, respiratory parameters began to deteriorate by day sp7-delta8-coGAA vector demonstrated increased hepatic
365. To sustain the therapeutic effect, it may be necessary to GAA secretion, reduced immunogenicity, and increased
administer a re-dose of the treatment. GAA activity in plasma and skeletal muscle [37].
To improve tissue-specific expression, especially in skeletal Neuropathology is a significant aspect of PD that requires
muscle, cardiac muscle, and motor neurons, a modified consideration in CNS therapy. The rAAV9, which exhibits
promoter for muscle creatine kinase (MCK) and desmin (DES) both muscle and CNS tropism, has been utilized in murine
was utilized. In pre-clinical studies, a construct containing an and non-human primate models [37,45]. Hordeaux et al.
AAV vector encoding human GAA expressed by MCK was demonstrated an improvement in both neurological and
administered into GAA-KO mice and non-human primates cardiac function in Gaa-/-mice following intrathecal
[37,44]. However, a high dose of this construct resulted in an administration of AAV9-CAG-hGAA [45]. Similar results
immune response and subsequent heart failure. The rAAV9- were observed in a study on mice models using the newly
DES-hGAA vector was used in randomized clinical trials isolated AAV-B1 serotype [46]. Preclinical studies have shown
(NCT02240407) after promising results from preclinical a satisfactory therapeutic effect in the brain and spinal cord
studies with DES promoter [37]. Patients with LOPD received using the synapsin I (Syn-I) promoter construct for neuron-
intramuscular injections of the vector in the tibial anterior specific expression (yfAAV9/3-Syn-I-hGAA) [37,47].
(TA) muscles [37,44]. Lentiviral-mediated HSPC gene therapy has also been
A liver-specific promoter (LPS) derived from the thyroid employed to treat LSD. The method consists of ex vivo-
hormone-binding globulin promoter and comprising an transduced HSPCs engrafting into the bone marrow niche
alpha-1 microglobulin/bikunin enhancer sequence was and differentiating into the full spectrum of haematopoietic
successfully utilised in preclinical studies with an AAV8- cells and microglia in the CNS [37,46]. Pre-transplant
hGAA vector to reduce glycogen deposits in the heart and bone marrow conditioning, including irradiation and
310 Journal of Pre-Clinical and Clinical Research 2024, Vol 18, No 4
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chemotherapeutic agents, is required [37]. Stok M. et al. vector design and transgene editing are necessary to enhance
reported positive outcomes in a preclinical study by using target tissue coverage. Gene editing can be challenging due
an LV expression cassette. This resulted in increased GAA to the wide range of mutations found in patients. Future
activity, reduced glycogen accumulation in the heart and therapeutic regimens may be influenced by new techniques
skeletal muscles, and detectable levels of GAA protein in for assessing innovative therapies, such as qMRI or the use of
microglia and astrocytes, suggesting cross-correction [48]. biomarkers such as miRNAs. After diagnosis, researchers may
Alternative molecular-based strategies, such as chemical face the main challenge of defining objective and quantitative
modification of antisense oligonucleotides (AONs) that are markers that are not affected by inter-observer variability.
insensitive to RNase-mediated degeneration, have shown Precise guidelines for the management and monitoring of
promise in preclinical settings by enhancing the endogenous the disease are also needed.
production of wild-type GAA, correcting aberrant splicing,
and mediating inclusion [49]. This approach, however, only
benefits a small subset of patients with similar gene variants. REFERENCES
Additionally, there may be concerns about compromising
safety, including the ability to mount an immune response 1. Taverna S, Cammarata G, Colomba P, et al. Pompe disease: patho­
genesis, molecular genetics and diagnosis. Aging (Albany NY).
to the capsid protein and transgene product, pre-existing 2020;12(15):15856–15874. doi:10.18632/aging.103794
neutralizing antibodies to AAV, inflammatory toxicity 2. Peruzzo P, Pavan E, Dardis A. Molecular genetics of Pompe disease: a
resulting from increased vector doses, complement activation, comprehensive overview. Ann Transl Med. 2019;7(13):278. doi:10.21037/
cytopenia, and hepatotoxicity [42,49]. To address these atm.2019.04.13
3. Stevens D, Milani-Nejad S, Mozaffar T. Pompe Disease: a Clinical,
concerns, short DNA oligonucleotides can be incorporated Diagnostic, and Therapeutic Overview. Curr Treat Options Neurol.
into vector genomes to antagonize TLR9 activation. This may 2022;24(11):573–588. doi:10.1007/s11940-022-00736-1 22
be beneficial in reducing TLR9-mediated immune responses, 4. Hahn A, Schänzer A. Long-term outcome and unmet needs in infantile-
allowing for higher doses to be infused into patients [37]. onset Pompe disease. Ann Transl Med. 2019;7(13):283. doi:10.21037/
Furthermore, the use of CRISPR tools has led to the atm.2019.04.70
5. Labella B, Cotti Piccinelli S, Risi B, et al. A Comprehensive Update on
development of novel mouse models that more accurately Late-Onset Pompe Disease. Biomolecules. 2023;13(9):1279. Published
mimic human disease phenotypes. For instance, the IOPD 2023 Aug 22. doi:10.3390/biom13091279
model utilizes sgRNA CRISPR-Cas9 homology-directed 6. Prakash S, Penn JD, Jackson KE, Dean LW. Newborn screening for
recombination to harbour the orthologous GAA mutation Pompe disease: Parental experiences and follow-up care for a late-onset
diagnosis. J Genet Couns. 2022;31(6):1404–1420. doi:10.1002/jgc4.1615
c.1826dupA (p.Y609*) [37,50]. These models may offer 7. El Haddad L, Khan M, Soufny R, et al. Monitoring and Management
valuable insights into the safety and efficacy of rAAV- of Respiratory Function in Pompe Disease: Current Perspectives. Ther
mediated gene transfer. Recent preclinical studies have used Clin Risk Manag. 2023;19:713–729. Published 2023 Sep 1. doi:10.2147/
PD rats generated by CRISPR/Cas to investigate the use of TCRM.S362871
a novel highly myotropic bioengineered capsid AAVMYO3 8. Herbert M, Case LE, Rairikar M, et al. Early-onset of symptoms
and clinical course of Pompe disease associated with the c.-32–13
and an optimized muscle-specific promoter in conjunction T > G variant. Mol Genet Metab. 2019;126(2):106–116. doi:10.1016/j.
with a transcriptional cis-regulatory element. Treatment with ymgme.2018.08.009
AAVMYO3-Gaa vectors resulted in a widespread expression 9. Nancy Leslie, Laurie Bailey. Pompe Disease. GeneReviews®, edited by
of GAA in muscle throughout the body. This resulted in a Adam MP, et al. University of Washington, Seattle, 31 August 2007.
10. Pfrimmer C, Smitka M, Muschol N, et al. Long-Term Outcome of
decrease in glycogen storage, an increase in muscle strength, Infantile Onset Pompe Disease Patients Treated with Enzyme
prevention of cardiomegaly, and an improved survival rate Replacement Therapy – Data from a German-Austrian Cohort. J
[50]. Neuromuscul Dis. 2024;11(1):167–177. doi:10.3233/JND-230164
11. Kenney-Jung D, Korlimarla A, Spiridigliozzi GA, et al. Severe CNS
involvement in a subset of long-term treated children with infantile-
onset Pompe disease. Mol Genet Metab. 2024;141(2):108119. doi:10.1016/j.
SUMMARY ymgme.2023.108119
12. Toscano A, Rodolico C, Musumeci O. Multisystem late onset Pompe
Although Pompe disease has been recognized as a clinical disease (LOPD): an update on clinical aspects. Ann Transl Med.
entity for almost a century, it remains a diagnostic and 2019;7(13):284. doi:10.21037/atm.2019.07.24
13. Jastrzębska A, Kostera-Pruszczyk A. Multisystem presentation of
therapeutic challenge for clinicians. Significant progress has Late Onset Pompe Disease: what every consulting neurologist should
been made in understanding the pathogenesis over the years, know. Neurol Neurochir Pol. 2023;57(2):143–150. doi:10.5603/PJNNS.
but the genetic mechanisms responsible for the diversity of a2022.0075
phenotypes are still not fully understood. Therefore, it is 14. Pompe disease GAA variant database; https://www.
important to report cases to the database to better understand pompevariantdatabase.nl/pompe_mutations_list.php?orderby=aMut_
ID1 (access: 2024.02.15)
the molecular basis of the pathomechanism of symptoms 15. Kroos M, Pomponio RJ, van Vliet L, et al. Update of the Pompe disease
and to analyze the prospects for patients. The NBS, which mutation database with 107 sequence variants and a format for severity
has been introduced in many countries, is an important rating. Hum Mutat. 2008;29(6):E13-E26. doi:10.1002/humu.20745
element in reducing the time from diagnosis to treatment 16. de Faria DOS, ‘t Groen SLMI, Hoogeveen-Westerveld M, et al. Update
of the Pompe variant database for the prediction of clinical phenotypes:
initiation. ERT is an undisputed success in PD, but it has Novel disease-associated variants, common sequence variants, and
limitations, including its inability to affect the CNS and results from newborn screening. Hum Mutat. 2021;42(2):119–134.
the immune response, which requires frequent re-dosing. doi:10.1002/humu.24148
To overcome these limitations, further research and new 17. Momosaki K, Kido J, Yoshida S, et al. Newborn screening for Pompe
therapeutic techniques are needed. Modified ERTs and disease in Japan: report and literature review of mutations in the GAA
gene in Japanese and Asian patients. J Hum Genet. 2019;64(8):741–755.
gene therapy are important areas of research. However, it is doi:10.1038/s10038-019-0603-7
crucial to thoroughly evaluate factors such as dose level, bio- 18. Kuperus E, van der Meijden JC, In ‘t Groen SLM, et al. The ACE I/D
distribution, and immunogenicity. Technological advances in polymorphism does not explain heterogeneity of natural course and
Journal of Pre-Clinical and Clinical Research 2024, Vol 18, No 4 311
Weronika Zegardło, Karolina Jankowiak, Bartłomiej Kwiatkowski, Zuzanna Kabała, Maria Nowakowska, Julia Osipowska et al. New horizons in understanding and treating…

response to enzyme replacement therapy in Pompe disease. PLoS 35. Li C, Desai AK, Gupta P, et al. Transforming the clinical outcome
One. 2018;13(12):e0208854. Published 2018 Dec 7. doi:10.1371/journal. in CRIM-negative infantile Pompe disease identified via newborn
pone.0208854 screening: the benefits of early treatment with enzyme replacement
19. van der Ploeg AT, Kruijshaar ME, Toscano A, et al. European consensus therapy and immune tolerance induction. Genet Med. 2021;23(5):845–
for starting and stopping enzyme replacement therapy in adult patients 855. doi:10.1038/s41436-020-01080-y
with Pompe disease: a 10-year experience. Eur J Neurol. 2017;24(6):768- 36. Yang CF, Yang CC, Liao HC, et al. Very Early Treatment for Infantile-
e31. doi:10.1111/ene.13285 Onset Pompe Disease Contributes to Better Outcomes. J Pediatr.
20. Chien YH, Hwu WL, Lee NC. Newborn screening: Taiwanese experience. 2016;169:174–80.e1. doi:10.1016/j.jpeds.2015.10.078
Ann Transl Med. 2019;7(13):281. doi:10.21037/atm.2019.05.47 37. Unnisa Z, Yoon JK, Schindler JW, Mason C, van Til NP. Gene Therapy
21. Sawada T, Kido J, Nakamura K. Newborn Screening for Pompe Disease. Developments for Pompe Disease. Biomedicines. 2022;10(2):302.
Int J Neonatal Screen. 2020;6(2):31. Published 2020 Apr 5. doi:10.3390/ Published 2022 Jan 28. doi:10.3390/biomedicines10020302
ijns6020031 38. U.S National Library of Medicine, database of privately and publicly
22. Feeney EJ, Austin S, Chien YH, et al. The value of muscle biopsies in funded clinical studies; https://clinicaltrials.gov/ (access: 2024.01.29)
Pompe disease: identifying lipofuscin inclusions in juvenile- and adult- 39. Diaz-Manera J, Kishnani PS, Kushlaf H, et al. Safety and efficacy of
onset patients. Acta Neuropathol Commun. 2014;2:2. Published 2014 avalglucosidase alfa versus alglucosidase alfa in patients with late-
Jan 2. doi:10.1186/2051-5960-2-2 onset Pompe disease (COMET): a phase 3, randomised, multicentre
23. Manganelli F, Ruggiero L. Clinical features of Pompe disease. Acta trial [published correction appears in Lancet Neurol. 2022
Myol. 2013;32(2):82–84. Apr;21(4):e4]. Lancet Neurol. 2021;20(12):1012–1026. doi:10.1016/S1474-
24. Reynolds TM, Tylee K, Booth K, Wierzbicki AS. PATHFINDER Project 4422(21)00241-6
Collaboration group; Collaborators and research nurses as listed 40. Blair HA. Cipaglucosidase Alfa: First Approval. Drugs. 2023;83(8):739–
below. Identification of patients with Pompé disease using routine 745. doi:10.1007/s40265-023-01886-5
pathology results: PATHFINDER (creatine kinase) study. J Clin Pathol. 41. Schoser B, Roberts M, Byrne BJ, et al. Safety and efficacy of cipaglucosidase
2019;72(12):805–809. doi:10.1136/jclinpath-2019-205711 alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset
25. Willis TA, Hollingsworth KG, Coombs A, et al. Quantitative muscle Pompe disease (PROPEL): an international, randomised, double-blind,
MRI as an assessment tool for monitoring disease progression in parallel-group, phase 3 trial [published correction appears in Lancet
LGMD2I: a multicentre longitudinal study. PLoS One. 2013;8(8):e70993. Neurol. 2023 Oct;22(10):e11]. Lancet Neurol. 2021;20(12):1027–1037.
Published 2013 Aug 14. doi:10.1371/journal.pone.0070993 doi:10.1016/S1474-4422(21)00331-8
26. Seiler A, Nöth U, Hok P, et al. Multiparametric Quantitative MRI in 42. Mingozzi F, High KA. Overcoming the Host Immune Response to
Neurological Diseases. Front Neurol. 2021;12:640239. Published 2021 Adeno-Associated Virus Gene Delivery Vectors: The Race Between
Mar 8. doi:10.3389/fneur.2021.640239 Clearance, Tolerance, Neutralization, and Escape. Annu Rev Virol.
27. O’Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, 2017;4(1):511–534. doi:10.1146/annurev-virology-101416-041936
Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 43. Smith BK, Martin AD, Lawson LA, et al. Inspiratory muscle conditioning
2018;9:402. Published 2018 Aug 3. doi:10.3389/fendo.2018.00402. 27 exercise and diaphragm gene therapy in Pompe disease: Clinical
28. Tarallo A, Carissimo A, Gatto F, et al. microRNAs as biomarkers in evidence of respiratory plasticity. Exp Neurol. 2017;287(Pt 2):216–224.
Pompe disease. Genet Med. 2019;21(3):591–600. doi:10.1038/s41436- doi:10.1016/j.expneurol.2016.07.013
018-0103-8 44. Eggers M, Vannoy CH, Huang J, et al. Muscle-directed gene
29. Ditters IAM, Huidekoper HH, Kruijshaar ME, et al. Effect of therapy corrects Pompe disease and uncovers species-specific GAA
alglucosidase alfa dosage on survival and walking ability in patients immunogenicity. EMBO Mol Med. 2022;14(1):e13968. doi:10.15252/
with classic infantile Pompe disease: a multicentre observational cohort emmm.202113968
study from the European Pompe Consortium. Lancet Child Adolesc 45. Hordeaux J, Dubreil L, Robveille C, et al. Long-term neurologic and
Health. 2022;6(1):28–37. doi:10.1016/S2352-4642(21)00308-4 cardiac correction by intrathecal gene therapy in Pompe disease. Acta
30. Bolano-Diaz C, Diaz-Manera J. Therapeutic Options for the Management Neuropathol Commun. 2017;5(1):66. Published 2017 Sep 6. doi:10.1186/
of Pompe Disease: Current Challenges and Clinical Evidence in s40478-017-0464-2
Therapeutics and Clinical Risk Management. Ther Clin Risk Manag. 46. Keeler AM, Zieger M, Todeasa SH, et al. Systemic Delivery of AAVB1-
2022;18:1099–1115. Published 2022 Dec 13. doi:10.2147/TCRM.S334232 GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe
31. Kishnani PS, Nicolino M, Voit T, et al. Chinese hamster ovary cell- Disease. Hum Gene Ther. 2019;30(1):57–68. doi:10.1089/hum.2018.016
derived recombinant human acid alpha-glucosidase in infantile- 47. Hordeaux J, Wang Q, Katz N, Buza EL, Bell P, Wilson JM. The
onset Pompe disease. J Pediatr. 2006;149(1):89–97. doi:10.1016/j. Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice.
jpeds.2006.02.035 Mol Ther. 2018;26(3):664–668. doi:10.1016/j.ymthe.2018.01.018
32. Chien YH, Tsai WH, Chang CL, et al. Earlier and higher dosing of 48. Stok M, de Boer H, Huston MW, et al. Lentiviral Hematopoietic Stem
alglucosidase alfa improve outcomes in patients with infantile-onset Cell Gene Therapy Corrects Murine Pompe Disease. Mol Ther Methods
Pompe disease: Evidence from real-world experiences. Mol Genet Clin Dev. 2020;17:1014–1025. Published 2020 May 4. doi:10.1016/j.
Metab Rep. 2020;23:100591. Published 2020 Apr 29. doi:10.1016/j. omtm.2020.04.023
ymgmr.2020.100591 49. van der Wal E, Bergsma AJ, Pijnenburg JM, van der Ploeg AT, Pijnappel
33. Khan AA, Case LE, Herbert M, et al. Higher dosing of alglucosidase alfa WWMP. Antisense Oligonucleotides Promote Exon Inclusion and
improves outcomes in children with Pompe disease: a clinical study and Correct the Common c.-32–13T>G GAA Splicing Variant in Pompe
review of the literature. Genet Med. 2020;22(5):898–907. doi:10.1038/ Disease. Mol Ther Nucleic Acids. 2017;7:90–100. doi:10.1016/j.
s41436-019-0738-0 omtn.2017.03.001
34. Ditters IAM, van Kooten HA, van der Beek NAME, van der Ploeg AT, 50. Muñoz S, Bertolin J, Jimenez V, et al. Treatment of infantile-onset Pompe
Huidekoper HH, van den Hout JMP. Are Anti-rhGAA Antibodies a disease in a rat model with muscle-directed AAV gene therapy. Mol
Determinant of Treatment Outcome in Adults with Late-Onset Pompe Metab. 2024;81:101899. doi:10.1016/j.molmet.2024.101899
Disease? A Systematic Review. Biomolecules. 2023;13(9):1414. Published
2023 Sep 19. doi:10.3390/biom13091414