rAAV1-CMV-hGAA for Pompe disease
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What is rAAV1-CMV-hGAA for Pompe disease?
rAAV1-CMV-hGAA is an experimental gene therapy being investigated as a potential treatment for Pompe disease patients with severe respiratory problems. It is designed to deliver a working version of the GAA gene, which is mutated in Pompe, to cells in the diaphragm. This is expected to improve breathing function.
The therapy was created by researchers at the University of Florida.
Therapy snapshot
| Treatment name: | rAAV1-CMV-hGAA |
| Administration: | Injections into the diaphragm |
| Clinical testing: | Completed a Phase 1/2 trial for Pompe disease |
How does rAAV1-CMV-hGAA work in Pompe disease?
Pompe disease is caused by mutations 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 this genetic disorder, dysfunction or absence of this 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 diaphragm — the main muscle that controls breathing — allowing production of a working enzyme in these muscle cells.
The gene therapy candidate uses a viral vector called adeno-associated virus serotype 1 (AAV1) to deliver its genetic cargo. It employs a genetic element adapted from the cytomegalovirus (CMV) that aims to drive robust GAA gene expression.
Results in a mouse model of Pompe disease indicated that this approach can improve muscle health and nerve cell output.
How will rAAV1-CMV-hGAA be administered in Pompe disease?
In a Phase 1/2 clinical trial, rAAV1-CMV-hGAA was given via a series of six injections into the diaphragm muscle. All were given on the same day, during a surgical procedure under general anesthesia. Participants were given one of two doses of the experimental gene therapy: 1 trillion or 5 trillion vector genomes.
rAAV1-CMV-hGAA in Pompe disease clinical trials
The University of Florida in the U.S. sponsored a Phase 1/2 clinical trial (NCT00976352) that enrolled nine children, ages 2-18, with Pompe. The children had ventilatory insufficiency — when the respiratory system cannot function effectively as a pump to oxygenate blood and eliminate carbon dioxide from the body — despite long-term use of enzyme replacement therapies. Such therapies are the standard treatment for Pompe disease.
To help with breathing, five children were on invasive mechanical ventilators full-time, and the other four required partially assisted ventilation. All participants underwent a surgical procedure in which one of two doses of rAAV1-CMV-hGAA was injected into the diaphragm muscle, via three injections on each side of the diaphragm.
The study’s main goal was to evaluate the treatment’s safety in the first year after the injections. Results were generally positive, with no side effects related to the gene therapy reported. The surgical procedure led to several serious events, including pleural effusion, a buildup of fluid between the layers of tissue lining the lungs and chest. Half of these events were expected.
The most frequent anticipated adverse event was pain, which could be managed with medication. Other side effects related to the procedure included collapsed lung or lung bruising, all of which resolved with treatment or active surveillance.
One patient died of bleeding in the brain nearly four years after treatment. The cause of his bleeding was the toxic glycogen buildup that damaged the brain’s blood vessels. It was not related to the gene therapy or the administration procedure.
Trial results also showed that combining rAAV1-CMV-hGAA with breathing exercises — meant to strengthen the muscles needed to pull air into the lungs — led to benefits in motor function of the diaphragm. The benefits were particularly greater in children who were younger, had better neuromuscular function before treatment, and used daily mechanical ventilation for fewer hours. No benefits were seen with exercise alone.
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.
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 were:
- pain, mainly in the shoulders and/or hips
- collapsed lung, called a pneumothorax
- bruising in the lung tissue, also known as a lung contusion.
Pompe Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about rAAV1-CMV-hGAA
rAAV1-CMV-hGAA is a gene therapy still in testing and not yet approved for people with Pompe disease. It is designed to deliver a working copy of the GAA gene — whose mutations cause Pompe — to the diaphragm muscle. Data from a Phase 1/2 clinical trial suggest the therapy may improve breathing function.
rAAV1-CMV-hGAA is in the early stages of clinical testing. The therapy has shown encouraging results in a Phase 1/2 clinical trial, but more advanced trials will be needed to establish its safety and efficacy. Thus, it is too early to say if or when the gene therapy might be approved in the U.S.
The only clinical trial that tested rAAV1-CMV-hGAA so far has not included patients who were pregnant or breastfeeding, so it is not known whether the gene therapy is safe for use during pregnancy.
In clinical trials, children with Pompe disease have experienced significant improvements in some measures of breathing function about six months after treatment. However, the efficacy of rAAV1-CMV-hGAA is still poorly established, and additional clinical trials will be needed to better understand when this gene therapy may lead to clinical benefit.
Hair loss and weight gain have not been reported as side effects of rAAV1-CMV-hGAA. Patients who experience any unexpected adverse events after starting a new treatment should speak with their healthcare providers.
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