rAAV9-DES-hGAA for Pompe disease

Last updated Sept. 8, 2022, by Marisa Wexler, MS

✅ Fact-checked by José Lopes, PhD

What is rAAV9-DES-hGAA for Pompe disease?

rAAV9-DES-hGAA is an experimental gene therapy designed for all forms of Pompe disease. It was originally created by researchers at the University of Florida, then developed by Florida spin-off company Lacerta Therapeutics, which licensed the therapy to Sarepta Therapeutics in 2018.

The gene therapy is currently in the earliest stages of preclinical development, according to Sarepta.

How does rAAV9-DES-hGAA work?

In Pompe disease, there is a mutation in the GAA gene that encodes for the acid alpha-glucosidase enzyme, which is responsible for breaking down a complex sugar called glycogen. The mutation causes the enzyme not to function properly, leading to the abnormal accumulation of glycogen inside cells.

rAAV9-DES-hGAA is designed to deliver a working version of the GAA gene to the body’s cells, allowing them to produce normal amounts of the enzyme to facilitate glycogen clearance.

The gene therapy delivers its payload using an engineered version of the adeno-associated virus serotype 9 (AAV9) that has been rendered harmless. The therapy delivers the GAA gene alongside a promoter sequence called DES, which normally helps to control the production of a muscle protein called desmin. This region is expected to help promote the expression of the gene in muscle tissue.

Studies in animal models of Pompe disease showed that rAAV9-DES-hGAA can be effective in improving breathing and heart function when injected into the pleural cavity (the space between the pleura, a sheet of tissue that wraps around the outside of the lungs and lines the inside of the chest cavity).

How was rAAV9-DES-hGAA administered?

In a Phase 1 clinical trial, rAAV9-DES-hGAA was administered via an injection into the tibialis anterior (TA) — a muscle in the lower leg — at a fixed dosage of 46 trillion vector genomes per TA.

How was rAAV9-DES-hGAA tested in clinical trials?

A Phase 1 clinical trial (NCT02240407) sponsored by the University of Florida tested rAAV9-DES-hGAA in adults (ages 18 to 50) with late-onset Pompe disease. Each participant was treated with rAAV9-DES-hGAA administered directly into a muscle of the lower leg, with two injections of the therapy into either leg given four months apart. Before the first injection, participants underwent a regimen to prevent an immune response against the gene therapy’s viral vector and the therapeutic gene.

The study, which is now complete, enrolled two participants. Preliminary data suggested that the immune-suppressing regimen prevented the development of antibodies against the AAV9 vector and the copy of GAA it delivers.


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