rAAV1-CMV-hGAA for Pompe disease

Last updated Sept. 6, 2022, by Marisa Wexler, MS

✅ Fact-checked by José Lopes, PhD

What is rAAV1-CMV-hGAA for Pompe disease?

rAAV1-CMV-hGAA is an investigational gene therapy for Pompe disease that was created by researchers at the University of Florida.

How does rAAV1-CMV-hGAA work?

Pompe disease is caused by a mutation in the GAA gene. This gene provides instructions for making an enzyme called acid alpha-glucosidase, which is needed to break down a complex sugar molecule called glycogen. In Pompe, dysfunction of the enzyme results in the toxic buildup of glycogen in the body’s cells.

rAAV1-CMV-hGAA is designed to deliver a functional version of the GAA gene to the body’s cells, allowing production of a working enzyme and ultimately clearing toxic glycogen.

The experimental gene therapy uses a viral vector called adeno-associated virus serotype 1 (AAV1) to deliver its genetic cargo. Expression of the GAA gene is controlled by a genetic element adapted from human cytomegalovirus (CMV) that aims to drive rapid and robust gene expression in all body tissues except the liver.

How is rAAV1-CMV-hGAA administered?

In a Phase 1/2 clinical trial, rAAV1-CMV-hGAA was administered via a series of injections into the diaphragm — the main muscle that controls breathing — during a surgical procedure under general anesthesia. Participants were given one of two doses of the experimental gene therapy, either 1 trillion or 5 trillion vector genomes.

How was rAAV1-CMV-hGAA tested in Pompe clinical trials?

The University of Florida sponsored a Phase 1/2 clinical trial (NCT00976352) that enrolled children with Pompe disease whose symptoms included difficulty breathing (ventilatory insufficiency) despite long-term use of enzyme replacement therapies, the current standard treatment for Pompe. All participants used ventilators to help them breathe — five were on invasive mechanical ventilators full-time, and the other four required partially assisted ventilation.

All the participants underwent a surgical procedure where one of two doses of rAAV1-CMV-hGAA was injected into the diaphragm. The study’s main goal was to evaluate the therapy’s safety. Results were generally positive, with no adverse events (side effects) related to the gene therapy reported. The surgical procedure led to several serious events, including pain and collapsed lung, but these were mainly expected and could be managed.

One patient died of bleeding in the brain nearly four years after treatment. The cause of death was attributed to toxic glycogen buildup damaging the brain’s blood vessels, and was not related to the gene therapy or the administration procedure.

Data from the first five trial participants showed that unassisted tidal volume — a measure of how much air is moved in and out of the lungs during a breath — increased significantly, by a median of 28.8% at 180 days (half a year) after treatment with rAAV1-CMV-hGAA. The amount of time patients could breathe unassisted increased markedly, by 425% on average, though the change was not statistically significant.

What were common side effects of rAAV1-CMV-hGAA?

In the Phase 1/2 trial, no side effects directly related to rAAV1-CMV-hGAA were reported.

The most common complications related to the surgical administration procedure in the clinical trial were:

  • pain, mainly in the shoulders and/or hips
  • pneumothorax (collapsed lung)
  • lung contusion (bruising in the lung tissue)


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