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Pompe Disease

Recent research efforts aimed at curing Pompe Disease.

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Français — Maladie de Pompe

Pompe Disease

Overview

Pompe disease is a rare inherited disorder caused by harmful changes in both copies of the GAA gene, which normally makes acid alpha-glucosidase (GAA), an enzyme that clears glycogen from lysosomes—the cell’s recycling compartments. Without enough GAA, glycogen accumulates, especially in heart, skeletal, and breathing muscles. The severe infantile-onset form usually begins in the first year of life with profound weakness, feeding difficulty, enlarged heart muscle, and respiratory failure; untreated disease progresses rapidly. Later-onset Pompe disease can appear from childhood through adulthood and more commonly causes gradually worsening hip-and-shoulder weakness and diaphragm weakness, sometimes leading to wheelchair dependence or respiratory failure. GeneReviews: Pompe Disease

Current care is not curative. It centers on lifelong intravenous enzyme-replacement therapy (ERT), which supplies manufactured GAA, plus specialized heart, respiratory, nutrition, rehabilitation, and genetic care. Available ERT options include alglucosidase alfa; avalglucosidase alfa for later-onset disease in people older than one year; and cipaglucosidase alfa with the enzyme stabilizer miglustat for certain adults with later-onset disease who are not improving on current ERT. Infants who make no native GAA protein—called CRIM-negative patients—also need early immune-tolerance treatment because they are at high risk of developing antibodies against infused enzyme. GeneReviews: Pompe Disease

Scope of Recent Research (2020–present)

Research since 2020 has been highly active, with the leading curative strategy being one-time gene replacement: delivering a working GAA gene so the body can produce its own enzyme continuously. The central questions are whether gene therapy can reach enough skeletal muscle, heart, and nervous-system tissue; safely manage immune responses; remain durable as children grow; and ultimately eliminate the need for ERT. Early human data now show biological activity and encouraging clinical signals, but the evidence remains too small and short-term to establish a cure. Phase I liver-depot gene therapy AAV9 gene therapy in infantile-onset Pompe disease

Major Breakthroughs and Emerging Therapies

AAV gene replacement. Most clinical gene-therapy programs use adeno-associated virus (AAV), a modified viral delivery vehicle carrying a functional GAA DNA sequence. Liver-directed approaches turn the liver into a long-term “factory” that secretes GAA into blood for uptake by other tissues. In a 2023 phase 1 study of AAV2/8-LSPhGAA, also called ACTUS-101, three adults with later-onset Pompe disease had sustained blood GAA activity after one infusion and stopped biweekly ERT after week 26 under the study protocol; muscle GAA activity increased by week 52, although glycogen in two of three muscle biopsies had not changed at week 24. Phase I liver-depot gene therapy

AAV programs are also targeting muscle and multiple organs directly. In a 2025 report, four infants with infantile-onset Pompe disease received a single intravenous infusion of the AAV9-based therapy GC301 after stopping ERT. Three surviving participants showed improvement in cardiac measures and motor function through 52 weeks, while one participant was withdrawn and subsequently died; anti-GAA antibodies were not detected during follow-up. AAV9 gene therapy in infantile-onset Pompe disease A subsequent 2026 single-arm study enrolled six older children previously treated with 10 to 98 ERT cycles. All remained ventilator-free over one year, muscle biopsies in three children showed increased GAA activity and less glycogen, and several achieved new motor milestones; however, cardiac structure and lung function did not show further improvement. GC301 after ERT discontinuation

Blood stem-cell gene therapy. A separate preclinical approach collects a person’s own blood-forming stem and progenitor cells, adds a functional GAA gene using a lentiviral vector outside the body, and reinfuses the corrected cells after conditioning treatment. The goal is durable enzyme production and, potentially, migration of corrected immune cells into the nervous system. In a 2020 mouse study, this approach reduced glycogen accumulation and improved heart and muscle function six months after treatment. Lentiviral HSPC gene therapy in mice A 2024 study further reported correction of muscle and neurological manifestations in Pompe mice, strengthening the rationale for eventual clinical translation but not yet establishing safety or benefit in people. Preclinical HSPC gene therapy

Improved enzyme therapies and gene editing. Improved ERT is not a cure, but it remains important both for present-day care and as a bridge to gene therapy. Avalglucosidase alfa was designed for better cellular uptake and was noninferior to alglucosidase alfa for respiratory function in the phase 3 COMET trial. COMET phase 3 trial Cipaglucosidase alfa is engineered for mannose-6-phosphate receptor uptake, while miglustat stabilizes the enzyme in circulation; in the phase 3 PROPEL study, the combination did not meet its overall superiority endpoint on the six-minute walk test, but it remains an approved option for a defined group of adults with later-onset disease. PROPEL phase 3 trial Gene editing is earlier still: CRISPR-based correction of patient-derived induced pluripotent stem cells has demonstrated restoration of GAA expression and enzyme cross-correction in laboratory models, but no gene-editing treatment for Pompe disease has entered clinical testing. Genome-editing strategies in Pompe iPSCs

Clinical Trials and Experimental Approaches

The completed phase 1 ACTUS-101 study, sponsored by AskBio, tested liver-directed AAV2/8 gene transfer in adults with later-onset Pompe disease. Its first published low-dose cohort included three participants, and the trial registry now lists the study as completed. Phase I liver-depot gene therapy ACTUS-101 trial record A separate Astellas-sponsored phase 1/2 study, FORTIS, is evaluating AT845 (zocaglusagene nuzaparvovec), an AAV8 vector designed to express GAA in muscle, in adults with later-onset Pompe disease. FORTIS trial record Preliminary conference data through two years in the first four treated participants were reported in 2026, but functional analyses remained ongoing and should be interpreted as preliminary. FORTIS two-year conference abstract

GC301 is being tested in both infantile- and later-onset disease. The published infantile studies described above were small, investigator-initiated, open-label studies; a phase 1/2 later-onset GC301 study began in 2024 and plans to assess safety, tolerability, and efficacy in participants aged six years or older. GC301 later-onset trial record Safety surveillance remains essential: a 2026 case report described sensory neuronopathy in a 49-year-old participant in the FORTIS AT845 study, illustrating why neurological, liver, immune, and long-term follow-up data are indispensable for systemic AAV therapies. Sensory neuronopathy after AT845

Methodologies and Scientific Approaches

Researchers use GAA-knockout mice, patient-derived cells, and increasingly sophisticated clinical measurements to test whether candidate therapies correct the underlying enzyme deficit and improve function. Key laboratory measures include GAA activity, glycogen content in muscle and other tissues, vector DNA levels, antibody and T-cell responses, and tissue pathology. Clinical studies pair these biomarkers with heart imaging, lung function, six-minute walking distance, motor-development scales, muscle MRI, and patient-reported outcomes. GeneReviews: Pompe Disease FORTIS trial record

The delivery platform is central to the research. Liver-directed AAV vectors aim to secrete enzyme systemically at relatively modest doses, whereas muscle-directed AAV vectors seek direct correction of skeletal muscle. AAV9 is attractive for infantile disease because it can reach heart, skeletal muscle, and the central nervous system in preclinical models; lentiviral blood-stem-cell approaches instead rely on corrected cells as a sustained enzyme source and possible route to the nervous system. AAV9 gene therapy in infantile-onset Pompe disease Preclinical HSPC gene therapy

Leading Institutions and Funding

Duke University School of Medicine and AskBio have been central to liver-directed AAV development through the ACTUS-101 program; the 2023 phase 1 publication included investigators from Duke, AskBio, the University of Pennsylvania, and Duke Clinical Research Institute. Phase I liver-depot gene therapy Astellas Gene Therapies sponsors the FORTIS AT845 study, while investigators at the Seventh Medical Center of the Chinese PLA General Hospital and Genecradle Therapeutics developed and tested GC301. FORTIS trial record AAV9 gene therapy in infantile-onset Pompe disease University College London–linked investigators and international collaborators are advancing lentiviral blood-stem-cell strategies in preclinical work. Preclinical HSPC gene therapy

Funding comes from industry-sponsored development, government research programs, and patient-focused philanthropy. The GC301 infant study reported support from the National Natural Science Foundation of China and National High Level Hospital Clinical Research Funding. AAV9 gene therapy in infantile-onset Pompe disease In the United States, the National Institute of Diabetes and Digestive and Kidney Diseases supports genetic-metabolic-disease research spanning animal models, small molecules, gene therapy, and ERT, while the Muscular Dystrophy Association reports more than $1 billion committed to neuromuscular research since its founding. NIDDK Genetic Metabolic Disease Program MDA research grants

Strengths, Limitations, and Challenges

The strongest evidence for a potentially disease-modifying, one-time treatment is that AAV gene therapy can produce sustained GAA activity after a single infusion, permit ERT withdrawal in some early studies, and show cardiac, motor, or muscle-biopsy improvements in selected participants. Phase I liver-depot gene therapy AAV9 gene therapy in infantile-onset Pompe disease Yet these trials have involved very few patients, lacked randomized controls, and have limited follow-up. In the 2026 GC301 study of previously ERT-treated children, cardiac and lung outcomes did not improve further, showing that enzyme restoration may not fully reverse established disease. GC301 after ERT discontinuation

The major obstacles are immune responses to the AAV capsid or GAA protein, limited ability to redose AAV after antibodies develop, variable delivery to skeletal muscle and the nervous system, potential liver or neurological toxicity, manufacturing complexity, and the uncertain durability of benefit over decades. The GC301 infant study found persistent AAV-binding antibodies after treatment, and the AT845-associated sensory-neuronopathy report underscores that rare or delayed adverse effects may emerge only with careful long-term monitoring. AAV9 gene therapy in infantile-onset Pompe disease Sensory neuronopathy after AT845

Outlook and Future Directions

As of August 8, 2026, Pompe disease is not cured by any approved therapy, but the field has moved from laboratory proof-of-concept to several human gene-replacement studies with early evidence of sustained enzyme production and clinical benefit in some participants. The next decisive milestones are larger and longer controlled studies; confirmation that patients can remain safely off ERT; durable preservation or improvement of respiratory, motor, cardiac, and neurological function; and evidence that AAV and stem-cell approaches can be delivered safely and equitably across the full range of Pompe disease. GC301 later-onset trial record FORTIS trial record

References

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