Promising study suggests AAV-based gene therapy can treat type I glutaric aciduria

Glutaric aciduria type I (GA-I) is an inherited disease caused by a mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. The global incidence of GA-I is estimated at 1/100,000, with approximately 75,000 cases worldwide.

Patients suffering from this disease find it difficult to digest proteins. This results in a buildup of excess glutaric acid, which damages the central nervous system (CNS). Symptoms usually appear when patients are still babies and include an abnormally large head, decreased muscle tone, and acute brain dysfunction. There is no cure available and without proper treatment the life expectancy is only 2-3 years. With treatment, such as diet control, carnitine supplements, and medical attention for acute attacks, some disease progression can be managed.

Lu Guo, a Ph.D. candidate at the Institute of Zoology, Chinese Academy of Sciences, undertook a study with her co-authors to explore the potential of adeno-associated virus (AAV) to treat AG-I patients. Their results have just been published in Fondamental research.

Guo says, “We exposed four-week-old mice with the disease to two consecutive days of a high-protein diet. The survival rate in the group that did not receive AAV was 40%, but in the group that received AAV directly. in their cerebrospinal fluid, the survival rate increased to 100 percent.”

The research team chose to go the AAV route because it has proven to be an effective treatment for a variety of genetic disorders. Guo says, “The advantage of AAV is that it can be delivered to a specific tissue or organ. While the GCDH gene is highly expressed in the liver and kidneys of GA-I patients, the main area of ​​the body affected by the disease is the CNS. That meant we had to decide where to deliver the AAV.”

For this aspect of the project, the team turned to the Egyptian bat for inspiration, as Guo explains. “The bat is specifically deficient in GCDH in its liver and kidneys. But while it has elevated levels of glutaric acid in its peripheral organs, levels in its central nervous system are normal and the bat leads healthy living. This led us to believe that delivering AAV to the CNS should be our priority.”

The team tested whether administering AAV to the CNS or peripheral organs influenced survival rates. As their initial research had suggested, its administration to the CNS contributed to a higher survival rate.

Corresponding author Wei Li adds, “The next step is to advance this drug to become a marketed drug and an investigator-initiated clinical trial is already underway. In the meantime, we are delighted that this project has received a Rare Pediatric Disease Designation (RPDD) from the Food and Drug Administration (FDA).”

This designation is designed to support rare diseases in children with unmet needs. Its purpose is to spur the development of new drugs for these conditions by spurring researchers to seek FDA approval for treatments.

Provided by KeAi Communications