Gene Therapy for the Treatment of Pompe Disease

Pompe disease is a rare, inherited metabolic disorder. Mutations in the acid alpha-glucosidase enzyme cause toxic buildup of cellular byproducts, leading to damage to multiple organs and tissues, particularly the muscles. Symptoms can appear within a few months of birth or may arise later in life. Affected babies commonly experience muscle weakness, poor muscle tone, and liver and heart defects that can lead to premature death in the first year of life. Later-onset forms of the disease can result in delayed motor skills and progressive muscle weakness, leading to breathing problems and respiratory failure. Enzyme replacement therapy is available, but outcomes vary. The lead collaborators have developed a gene therapy approach that aims to overcome the variability of current enzyme treatment. The purpose of this project is to support further preclinical development and enable clinical trials.

Scientific Synopsis

Pompe disease (also called acid maltase deficiency or glycogen storage disease type II) is a metabolic condition caused by a deficiency of acid alpha-glucosidase (GAA) enzyme activity in striated and smooth muscle. The GAA enzyme is active in the lysosomes, metabolizing glycogen into glucose. Mutations in the GAA gene prevent the enzyme from carrying out its normal function, leading to toxic accumulation of glycogen. Onset and severity of symptoms vary. More severe forms of the disease may arise within a few months after birth, marked by muscle weakness and poor muscle tone, failure to thrive, liver and heart defects, and serious breathing problems leading to premature death. Milder forms may arise in childhood, adolescence, or even adulthood, marked by progressive muscle weakness and breathing problems that can lead to respiratory failure.

Recombinant human GAA as an enzyme replacement therapy (ERT) is available, but its effectiveness varies. The ERT has been shown to ameliorate muscular and cardiac symptoms and increase overall survival rates, but the short half-life of GAA protein and the formation of antibody responses in some patients limits its utility. The lead collaborators have developed an adeno-associated virus (AAV) vector to transduce the GAA gene into the liver, enabling more continuous secretion of GAA protein. Preclinical studies have demonstrated uptake of the secreted GAA protein in heart and skeletal muscle tissues, associated with clearance of excess glycogen and improved muscle function. This project takes a novel approach of delivering a low dose of AAV-GAA to the liver to increase immune tolerance to GAA in patients.

Lead Collaborator

Duke University, Durham, NC
Dwight Koeberl, M.D., Ph.D.

Public Health Impact

Pompe disease is a genetic disorder that leads to premature death, typically from heart or respiratory failure. Although an enzyme replacement therapy is available, it is not appropriate for all patients. The ERT is costly, shows variable effectiveness in some patients, and requires frequent, lifelong administration. A gene therapy could yield a more consistently effective approach, potentially requiring only a single administration.


TRND scientists supported the manufacture of clinical-grade therapeutic vectors for use in the lead collaborator’s planned phase I trial in Pompe disease patients. During the collaboration with TRND, the AAV gene therapy technology was licensed by Asklepios BioPharmaceutical, Inc. AskBio formed a spin-out company, Actus Therapeutics, to continue clinical development and commercialization. The key preclinical support provided by TRND enabled the lead collaborator to successfully obtain funding for the phase I trial, which TRND co-funded through a cooperative agreement with the National Institute of Arthritis and Musculoskeletal and Skin Diseases. See, NCT03533673.