Pompe disease gene therapy is a novel, next-generation therapeutic approach for treating the disease. Gene therapy is a type of medical intervention that treats a genetic disease or halts and potentially reverses disease progression by correcting the underlying genetic cause. It alters the individual’s genetic makeup by replacing the faulty gene or adding a new gene with the correct DNA sequence to either cure the disease or improve the current functional status of the patient.1,2

Genes are directly transferred into a person’s cells using a vector, most commonly an adeno-associated virus (AAV). Risks of gene therapy using this viral method include possible infection caused by the virus and an immune system response. The risk of triggering an immune response is lower with gene therapy than with enzyme replacement therapy (ERT), however.3 The virus may also target the incorrect cells, which may damage healthy cells or contribute to cancer development.2

Due to the complexity of Pompe disease, which impacts multiple organ systems such as endothelial cells, motor neurons, and cardiac, skeletal, and smooth muscles, selection of desired target tissues for the AAV vector poses an important step in the delivery of gene therapy. Once the target tissue has been chosen, route of administration (intramuscular, intravenous, intrathecal, intracisternal, or intracerebroventricular), vector capsid serotype, and specific promoters on the AAV combine to achieve targeted gene therapy delivery and promote expression of the deficient enzyme.4   

Preclinical Trials 

Proof-of-concept preclinical trials in mice demonstrated the capacity of Pompe patient-derived cells treated with gene therapy to produce functional human acid alpha-glucosidase (GAA) enzyme and that these corrected enzymes could be effectively delivered to the lysosomes. In these preclinical trials, the AAV vectors successfully delivered and transduced the corrected genetic material into cardiac and skeletal muscles as well as neural tissue, improving the function in both muscles and nerves in mice with Pompe patient-derived cells.5  

Preliminary animal studies indicate that gene therapy possesses the potential to surmount the ERT half-life limitations caused by GAA ERT, which necessitates that the patient undergo frequent intravenous infusions and trips to the laboratory for treatment. ERT only delivers a certain amount of functional GAA enzyme at one time, and adequate GAA concentration levels deteriorate without continued replacement. In contrast, gene therapy has the potential to achieve a sustained replenishment of functional GAA enzyme in the blood.6 

Currently, 3 universities and 7 biotechnology companies are conducting preclinical and clinical trials to determine the efficacy and safety of gene therapy for individuals with Pompe disease. One literature review published in 2019 indicated that biotech companies—Sarepta, Amicus, Regeneron, and AvroBio—were conducting preclinical trials, while Actus, Audentes, and Spark had achieved varying degrees of clinical trial status.7

Amicus announced a collaboration with the University of Pennsylvania’s Perelman School of Medicine in Philadelphia for their preclinical Gene Therapy Program for Pompe disease.8 

AT845, a single-dose, muscle-directed gene therapy, demonstrated a robust, dose-dependent increase in GAA enzyme activity in mouse and nonhuman primate models that effectively improved function by clearing accumulated lysosomal glycogen without provoking immune responses.9

Clinical Trials

Clinical trials have begun to test gene therapy products in humans with Pompe disease.

Actus Therapeutics is currently in collaboration with Duke University to conduct a phase 1/2 clinical trial, ACT-CS101, to assess the safety and efficacy of gene therapy using an AAV vector that targets and transduces the corrected genetic material into liver cells in patients with Pompe disease.6,10 

Spark Therapeutics is in collaboration with the University of California, Irvine to conduct a phase 1/2 investigational, dose-escalation clinical trial, RESOLUTESM, assessing the safety and efficacy of a liver-directed, AAV gene therapy for individuals with late-onset Pompe disease.11,12 

Astellas Pharma recently acquired Audentes Therapeutics and is continuing the phase 1/2 clinical trial, FORTIS, to assess the efficacy and safety of AT845, a gene therapy for adults with late-onset Pompe disease. FORTIS is a multicenter clinical trial being conducted across 8 sites in the United States, Germany, and the United Kingdom.13,14


  1. What is gene therapy? MedlinePlus. Updated March 1, 2022. Accessed March 7, 2022.
  2. Gene therapy. Mayo Clinic. December 29, 2017. Accessed March 7, 2022. 
  3. Khanna S. Duke to begin clinical trials for Pompe disease gene therapy this fall. News release. Duke Department of Pediatrics; March 28, 2018.
  4. Salabarria SM, Nair J, Clement N, et al. Advancements in AAV-mediated gene therapy for Pompe disease. J Neuromuscul Dis. 2020;7(1):15-31. doi:10.3233/JND-190426
  5. Byrne BJ, Falk DJ, Pacak CA, et al. Pompe disease gene therapy. Hum Mol Genet. 2011;20(R1):R61-R68. doi:10.1093/hmg/ddr174
  6. Rosenberg M. Actus begins gene therapy trial for Pompe disease. News release. Duke Department of Pediatrics; February 1, 2019.
  7. Ronzitti G, Collaud F, Laforet P, Mingozzi F. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):287. doi:10.21037/atm.2019.04.67
  8. Programs & pipeline: Pompe disease. Amicus Therapeutics. Accessed March 7, 2022. 
  9. Eggers M, Vannoy CH, Huang J, et al. Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med. 2022;14(1):e13968. doi:10.15252/emmm.202113968
  10. AAV2/8-LSPhGAA in late-onset Pompe disease. ClinicalTrials.gov. May 23, 2018. Updated February 21, 2021. Accessed March 7, 2022. 
  11. Spark Therapeutics announces first participant dosed in phase 1/2 study of investigational gene therapy for late-onset Pompe disease. News release. Spark Therapeutics; February 1, 2021.
  12. A gene transfer study for late-onset Pompe disease (RESOLUTE). ClinicalTrials.gov. September 18, 2019. Updated February 21, 2022. Accessed March 7, 2022.
  13. Abdullah AI. First patient dosed in FORTIS trial of AT845 for LOPD. Pompe Disease News. April 13, 2021. Accessed March 7, 2022.
  14. Gene transfer study in patients with late onset Pompe disease (FORTIS). ClinicalTrials.gov. November 22, 2019. Updated August 27, 2021. Accessed March 7, 2022.

Reviewed by Harshi Dhingra, MD, on 3/5/2022.