What’s new and what’s next for gene therapy in Pompe disease?

Roger, Angela L.; Sethi, Ronit; Huston, Meredith L; Scarrow, Evelyn; Bao-Dai, Joy; Lai, Elias; Biswas, Debolina D.; Haddad, Léa El; Strickland, Laura M; Kishnani, Priya S.; ElMallah, Mai K.

doi:10.1080/14712598.2022.2067476

Cited by 6 publications

(8 citation statements)

References 193 publications

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“…Given the limited therapeutic efficacy of ERT in rescuing skeletal muscle pathology, multiple preclinical studies explored gene therapy using AAV vectors of different serotypes expressing GAA to deliver the transgene to skeletal muscle by local or systemic route (reviewed in refs. 17 – 19 ). The safety of the local (intradiaphragmatic) delivery was supported by the first clinical trial designed to improve respiratory insufficiency in ERT-treated patients with IOPD ( 21 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice

et al. 2023

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Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus–mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets — skeletal and cardiac muscles, the diaphragm, and the central nervous system — in both young and severely affected old Gaa -knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.

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Section: Discussionmentioning

confidence: 99%

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice

et al. 2023

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“…The development of next-generation ERTs and gene therapies for Pompe disease is crucial in order to address the limitations of current treatments and provide more effective options for patients [1,2,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. These advancements aim to overcome challenges such as poor distribution to muscles, reduced muscle uptake, interference from antibodies, and limited penetration of the blood-brain barrier.…”

Section: Am J Biomed Sci and Resmentioning

confidence: 99%

“…Promising developments have been made with neoGAA and AT-GAA, which have reached the pivotal stage of clinical development. The breakthrough therapy designation granted to AT-GAA by the FDA indicates its potential for substantial improvement over existing therapies [1,2,21,[24][25][26]33,35]. Gene therapy, as a single-administration curative treatment, holds great promise for Pompe disease based on preclinical data [1,2,21,[24][25][26]33,35].…”

Section: Am J Biomed Sci and Resmentioning

confidence: 99%

“…The breakthrough therapy designation granted to AT-GAA by the FDA indicates its potential for substantial improvement over existing therapies [1,2,21,[24][25][26]33,35]. Gene therapy, as a single-administration curative treatment, holds great promise for Pompe disease based on preclinical data [1,2,21,[24][25][26]33,35]. However, there are still significant challenges and questions that need to be addressed.…”

Section: Am J Biomed Sci and Resmentioning

confidence: 99%

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2023

AJBSR

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Pompe disease, acid maltase disease, is a rare, autosomal recessive inherited metabolic disorder from the group of lysosomal storage diseases, which is based on a genetically caused deficiency of an enzyme and is treatable by substitution of this enzyme. Pompe disease is also known as myopathy due to acid maltase deficiency, α-1,4-glucosidase deficiency or acid α-glucosidase deficiency, glycogen storage disease type II or glycogenosis type II. It is inherited in an autosomal recessive manner. When each parent carries one copy of the mutated gene the child will be affected by Pompe disease. Pompe disease is one of the metabolic myopathies and is a glycogen storage disease. The incidence of Pompe disease is estimated to be approximately 1:40,000-1:200000. The disease is due to a genetic deficiency or complete absence of the lysosomal Enzyme Acid α-glucosidase. GAA degrades glycogen to glucose, particularly in the lysosomes of muscle tissue. Due to the lack of enzyme, glycogen derived from autophagy accumulates in the lysosomes. As with other lysosomal storage diseases, the cells are affected in their function first, and increasingly as the disease progresses, the entire muscle tissue is affected. Once damage has occurred, it is usually irreversible. Three different types are known, an infantile form (IOPD), a non-classic IOPD without cardiac involvement and a late onset LOPD. IOPD patients show a GAA enzymatic activity of 1-3 %, in LOPD patients an enzyme activity of 2-40 % of GAA is present. Diagnosis will be confirmed by GAA enzyme analysis prenatally in amniotic fluid and postnatally by alpha 1-4 glucosidase activity in the blood. The later the disease appears the better it can be treated. This manuscript focuses on the present therapeutical options to treat Pompe disease in children and shed light on present molecular research curing the disease.

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“…Gene therapy using adeno-associated virus (AAV) to deliver a functional GAA gene is ideal for a monogenetic disease such as PD. 87 The first clinical trial investigating AAV-GAA gene therapy in PD was initiated in ventilator-dependent PD patients. 88 The study consisted of five patients from 2–18 years of age.…”

Section: Introductionmentioning

confidence: 99%

Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives

El Haddad,

Khan,

Soufny

et al. 2023

TCRM

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Pompe disease (PD) is a neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA) – a lysosomal enzyme responsible for hydrolyzing glycogen. GAA deficiency leads to accumulation of glycogen in lysosomes, causing cellular disruption. The severity of PD is directly related to the extent of GAA deficiency – if no or minimal GAA is produced, symptoms are severe and manifest in infancy, known as infantile onset PD (IOPD). If left untreated, infants with IOPD experience muscle hypotonia and cardio-respiratory failure leading to significant morbidity and mortality in the first year of life. In contrast, late-onset PD (LOPD) patients have more GAA activity and present later in life, but also have significant respiratory function decline. Despite FDA-approved enzyme replacement therapy, respiratory insufficiency remains a major cause of morbidity and mortality, emphasizing the importance of early detection and management of respiratory complications. These complications include impaired cough and airway clearance, respiratory muscle weakness, sleep-related breathing issues, and pulmonary infections. This review aims to provide an overview of the respiratory pathology, monitoring, and management of PD patients. In addition, we discuss the impact of novel approaches and therapies on respiratory function in PD.

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What’s new and what’s next for gene therapy in Pompe disease?

Cited by 6 publications

References 193 publications

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice

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Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives

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