rAAV9-DES-hGAA for Pompe disease
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What is rAAV9-DES-hGAA for Pompe disease?
An experimental gene therapy, meaning it replaces a faulty gene with a healthy one, rAAV9-DES-hGAA has been tested in clinical trials as a treatment for Pompe disease.
Pompe is caused by mutations in the GAA gene, and rAAV9-DES-hGAA is designed to provide a working version of that gene to cells in a lower leg muscle called the tibialis anterior. As such, the therapy is expected to improve muscle and nerve function in the treated limb.
rAAV9-DES-hGAA was originally created by researchers at the University of Florida, and then developed by the university’s spin-off company, Lacerta Therapeutics. It was licensed to Sarepta Therapeutics in 2018, but the company dropped out of the agreement in 2023.
No further updates about this developmental program have since been released.
Therapy snapshot
| Treatment name: | rAAV9-DES-hGAA |
| Administration: | Injection into the tibialis anterior, a lower leg muscle |
| Clinical testing: | Completed a Phase 1 trial for late-onset Pompe disease |
How does rAAV9-DES-hGAA work in Pompe disease?
Pompe disease results from mutations in the GAA gene, which codes for a similarly named enzyme known as acid alpha-glucosidase, or GAA. This enzyme is responsible for breaking down a complex sugar called glycogen that is a key energy source for muscle cells. An absence or deficiency of the GAA enzyme leads to the toxic accumulation of glycogen inside cells.
rAAV9-DES-hGAA is designed to deliver a working version of the GAA gene to muscle 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 GAA gene is delivered 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 an animal model of Pompe disease showed that rAAV9-DES-hGAA can effectively improve breathing and heart function when injected into the pleural cavity, which is the fluid-filled space that surrounds the lungs.
How will rAAV9-DES-hGAA be administered in Pompe disease?
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 required for the upward flexion or bending movement of the foot during walking. It was delivered at a fixed dosage of 46 trillion vector genomes per TA.
Patients also received immunosuppressive medications (rituximab and sirolimus) to eliminate immune B-cells prior to the gene therapy. This approach is believed to prevent the development of neutralizing antibodies against the therapy and enable repeat dosing.
rAAV9-DES-hGAA in clinical trials
A Phase 1 clinical trial (NCT02240407), sponsored by the University of Florida and completed in 2021, tested rAAV9-DES-hGAA in two adults, ages 18-50, with late-onset Pompe disease.
Each participant received two intramuscular injections of rAAV9-DES-hGAA, administered directly into the lower leg muscle tibialis anterior. The patients initially received one injection in one leg and a control treatment in the other, and treatments were given to the opposite leg four months later. The trial allowed anyone on enzyme replacement therapy prior to starting the study to continue receiving those medications for its duration.
Before the first injection, the participants underwent an immunosuppressive regimen containing rituximab and sirolimus to prevent an immune response against the gene therapy’s viral vector and the therapeutic gene.
Preliminary data suggested that the immune-suppressing regimen could safely and effectively prevent the development of antibodies against the AAV9 vector and the copy of GAA it delivers.
The trial’s main goal was to test the approach’s safety. Secondary measures included changes in muscle and neuronal function, walking ability, and muscle strength, as well as glycogen clearance in the treated muscle. However, efficacy and safety data have not been reported to date.
Common side effects of rAAV1-DES-hGAA
There are no available data regarding the safety of rAAV1-DES-hGAA in Pompe disease clinical trials.
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FAQs about rAAV1-DES-hGAA
rAAV9-DES-hGAA is an experimental gene therapy that’s not yet approved for Pompe disease. The treatment is designed to deliver a working copy of the GAA gene — whose mutations cause Pompe — to the tibialis anterior, a muscle in the lower leg. This is expected to improve muscle and nerve function, but clinical data for rAAV9-DES-hGAA are not yet available to confirm its benefits.
rAAV9-DES-hGAA is in the early stages of clinical testing. Its safety and efficacy are yet to be established, so it is too early to say if or when the gene therapy might be approved in the U.S.
The Phase 1 clinical trial that tested rAAV9-DES-hGAA in Pompe patients did not include people who were pregnant or breastfeeding, so it is not known whether the gene therapy is safe for use during pregnancy.
Efficacy results for rAAV9-DES-hGAA, including how early it may provide potential clinical benefits to patients, have not yet been reported.
Safety data from the clinical trial testing rAAV1-DES-hGAA in Pompe disease have not been made available yet, so it’s not known if the therapy can result in hair loss or weight gain. Patients who experience any unexpected adverse events after starting a new treatment should always speak with their healthcare providers.
