Gene Therapy for Pompe Disease

Pompe disease is a rare inherited disorder that causes progressive muscle damage and weakness. The condition is caused by mutations in the GAA gene, which provides instructions for an enzyme called acid alpha-glucosidase that is involved in breaking down a substance called glycogen.

Glycogen is a large complex sugar stored in muscles and broken down to produce smaller sugars like glucose that are used as the main energy source for cells. When there is reduced or no functional acid alpha-glucosidase enzyme, glycogen builds up to toxic levels and cannot be used as an energy source. This causes damage to muscles and other tissues throughout the body.

There is currently no cure for Pompe disease, which can often be fatal especially in the infantile-onset form. However, research is ongoing to find new treatments for the disease, and approaches such as gene therapy have produced promising results.

What is gene therapy?

One of the most commonly used therapies to treat Pompe disease is enzyme replacement therapy, which supplies the body with a functioning copy of the acid alpha-glucosidase enzyme. However, as the body breaks down the enzyme, the treatment needs to be frequently readministered. Moreover, it does not address the underlying problem — the fact that the body cannot produce the enzyme itself, and may cause the body to mount an immune response against the injected enzyme.

Gene therapy aims to restore the body’s ability to produce functional acid alpha-glucosidase enzyme on its own by providing cells with a functioning copy of the GAA gene.

A functioning copy of a gene is commonly delivered to the body using a modified virus called an adeno-associated virus (AAV) as a vector. A vector is a vehicle used to transport a gene inside cells. The AAV vector has had its disease-causing genes removed so that it is no longer dangerous, and the gene of interest added — in this case, GAA. As a virus, it can still integrate the gene into the genome of the patient, providing cells with a new healthy copy of GAA that can be used to produce the functional enzyme. This can be targeted to specific tissues in the body, including affected organs such as the diaphragm, for example, to improve breathing capacity.

Gene therapy in clinical trials

There are several research groups investigating gene therapy in Pompe disease. Some of these potential therapies have already been tested in clinical trials while others are in the preclinical stage and are being tested in animals.

Researchers at the University of Florida have completed an initial Phase 1/2 clinical trial (NCT00976352) to assess the safety of rAAV1-CMV-hGAA, an investigational gene therapy using an AAV vector administered through an injection directly into the diaphragm. This is intended to improve respiratory function, one of the most common causes of death in Pompe disease. The trial enrolled nine ventilator-dependent children, ages 3 to 14, with Pompe disease at a single site in Florida. Results of the trial, published in the journal Human Gene Therapy, suggested that the treatment is safe and tolerated in children with Pompe disease. Further trials are planned to test the effectiveness of the therapy and different delivery strategies.

The University of Florida is also conducting a Phase 1 clinical trial (NCT02240407) to test another gene therapy candidate, rAAV9-DES-hGAA, combined with immune modulation therapies, to reduce the chance of a damaging immune response against the treatment. The trial will take place at a single site at the University of Florida, and is currently recruiting up to nine participants with late-onset Pompe disease, ages 18 to 50.

Researchers at Duke University are investigating gene therapy for Pompe disease as part of the National Institutes of Health’s (NIH) Therapeutics for Rare and Neglected Diseases (TRND) program. Up to 20 adults with late-onset Pompe disease are currently being recruited at Duke’s Medical Center in Durham, North Carolina, to be screened for eligibility in a future trial to investigate their AAV-based gene therapy approach (NCT03285126).

In September 2017, AVROBIO announced the expansion of their gene therapy program to include Pompe disease. The new program, called AVR-RD-03, is currently in the proof-of-concept preclinical stage in a mouse model of Pompe disease. The company hopes to use the results of this study to provide evidence to file an investigational new drug application with the U.S. Food and Drug Administration for human clinical trials.


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