rAAV9-DES-hGAA is a type of gene therapy that is currently being developed by a team of researchers at the University of Florida to treat Pompe disease.

How rAAV9-DES-hGAA works

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 to not function properly, leading to the abnormal accumulation of glycogen inside cells.

rAAV9-DES-hGAA is a type of virus called an adeno-associated virus (AAV) that has been rendered harmless and that carries a healthy copy of the GAA gene. The virus also contains a DNA fragment called a promoter that may increase the specificity of the treatment in targeting the correct cells.

When rAAV9-DES-hGAA is injected into the body, the inactivated virus inserts the healthy copy of the GAA gene into cells, allowing them to produce normal amounts of GAA enzyme.

Advantages of rAAV9-DES-hGAA over current treatments

Current treatments for Pompe involve giving patients functional acid alpha-glucosidase enzyme as an injection, an approach known as enzyme replacement therapy (ERT). For this treatment, the enzyme must usually be given as bi-weekly injections throughout a patient’s life, which can be very inconvenient. rAAV9-DES-hGAA, on the other hand, could potentially cure the disease by allowing the body to make its own functional acid alpha-glucosidase enzyme.

Repeated ERT also may cause the body to develop neutralizing antibodies against the injected enzyme, interfering with its effectiveness. To counter this problem, ERT is usually given with immune-modulating therapies in order to suppress the development of these detrimental antibodies. In the case of rAAV9-DES-hGAA therapy, because the body makes its own acid alpha-glucosidase enzyme, it is less likely that the immune system will recognize it as foreign and attack it. However, this may still happen and rAAV9-DES-hGAA can also be given with immune-modulating therapies.

Finally, ERT does not adequately correct glycogen accumulation problems in nerve cells and in the brain. That’s because the injected enzyme cannot cross the blood-brain barrier, a semipermeable membrane separating the blood from the fluid surrounding the brain and spinal cord. This is also thought to account for why ERT fails to prevent breathing problems in those with Pompe. rAAV9-DES-hGAA has the advantage of potentially treating nerve damage in Pompe disease and preventing severe breathing problems.

rAAV9-DES-hGAA in clinical trials

Studies in animal models of Pompe disease showed that rAAV9-DES-hGAA can be effective in improving breathing and heart problems when injected into the diaphragm.

A Phase 1/2 clinical trial (NCT02240407) is now investigating the effect of rAAV9-DES-hGAA in up to nine patients with adult-onset Pompe disease, ages 18 to 50.

During the trial, one group of patients will first receive injections of the immune modulating agents Rituxan and rapamycin for seven consecutive days to suppress their B-cells, which are responsible for producing neutralizing antibodies, before receiving the first injection of rAAV9-DES-hGAA directly into the muscle.

Four months later, patients will receive the same seven-day course of immune modulating agents followed by a single rAAV9-DES-hGAA injection at a different injection site. Each treatment injection will be given together with the anti-allergy medication diphenhydramine and the pain-killer acetaminophen. During the four months between treatment injections, patients will also be given monthly doses of immune globulin to re-boost the immune system.

Another group of patients will act as controls and will receive the exact same treatment protocol, but replacing the rAAV9-DES-hGAA molecule with an inactive compound, or placebo.

Throughout the study period, patients will be closely monitored to determine the treatment’s effects on muscle function as well as its safety and distribution in the body.

The trial is currently recruiting participants in Florida and is expected to end in June 2019.

Further details

The same research team has previously developed rAAV1-CMV-hGAA, another gene therapy with similar therapeutic effects, which has successfully completed a Phase 1/2 clinical trial (NCT00976352). Trial results showed it to be safe and well-tolerated in children with Pompe disease.


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