Alzheimer’s Gene Therapy Trial Launched in San Diego

Alzheimers disease, illustration

Researchers based at the University of California San Diego have launched a Phase I trial of a gene therapy for early Alzheimer’s disease (AD) and mild cognitive impairment.

The trial will build on similar trials carried out by the same team, but will use a different protein and make use of recent advances in gene therapy techniques to improve its chances of success.

A previous Phase I study carried out by the same team involved injecting nerve growth factor (NGF) into the brains of eight individuals with mild Alzheimer’s disease to assess if the treatment was safe and triggered cognitive improvement.

While the NGF treatment appeared safe and did seem to trigger some nerve growth, cognitive improvement was not highly significant, perhaps due to vector delivery problems.

Mark Tuszynski, M.D., Ph.D., a professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, led the original study and is in charge of the new Phase I trial, which is testing a different protein—brain-derived neurotrophic factor or BDNF. This protein is produced throughout a person’s life in the entorhinal cortex in the brain, which is involved in memory formation, and is present at lower than normal levels in people with Alzheimer’s.

“The BDNF gene therapy trial in Alzheimer’s disease represents an advance over the earlier NGF trial,” explained Tuszynski. “BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

Since the NGF trial, Tuszynski and colleagues have tested the efficacy of BDNF as a possible therapy for Alzheimer’s disease in animal models.

“We found that delivering BDNF to the part of the brain that is affected earliest in Alzheimer’s disease… was able to reverse the loss of connections and to protect from ongoing cell degeneration. These benefits were observed in aged rats, aged monkeys and amyloid mice,” he explained.

BDNF is a large protein and because of this will not easily fit through the blood-brain barrier. Tuszynski and team will use a modified adeno-associated viral vector (AAV2), a non-pathogenic virus commonly used for other types of gene therapy, to transport the protein to the target areas of the brain via direct injection. Precision is important for this therapy as freely circulating BDNF can cause seizures if healthy brain tissue is exposed to the protein.

Overall, the trial will take place over approximately three years. The researchers plan to recruit 12 participants with early Alzheimer’s disease, or mild cognitive impairment (which precedes full-blown dementia), who will receive the AAV2-BDNF therapy and 12 controls.

Despite large amounts of investment over many years, Alzheimer’s disease has few effective treatments and no one has yet been able to reverse its effects. Many researchers and companies have tried to develop therapies, but most have failed, several as late as Phase III.

It’s possible that gene therapy could succeed where other therapies have failed. Tuszynski is hoping to build on the recent success of gene therapies such as the FDA approved eye gene therapy Luxturna and CAR T-cell therapy Kymriah.

“BDNF gene therapy has the potential, unlike other Alzheimer’s disease therapies currently under development, to rebuild brain circuits, slow cell loss and stimulate cell function. We are looking forward to observing the effects of this new effort in patients with Alzheimer’s disease and mild cognitive impairment,” he concluded.

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