Clinical Trial Will Evaluate Gene Therapy for Alzheimer’s Disease

A team from UC San Diego School of Medicine will conduct a clinical trial to assess the value of a gene therapy to deliver a protein into the brains of people with Alzheimer’s disease.

The protein is called brain-derived neurotrophic factor (BDNF) and is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons. These proteins also promote growth and differentiation of new neurons and synapses. BDNF is particularly critical in brain regions susceptible to degeneration in Alzheimer’s.

Previous research done in animal models suggested that BDNF may slow, prevent, or reverse progression of Alzheimer’s disease and brain cell degeneration.

“We found that delivering BDNF to the part of the brain that is affected earliest in Alzheimer’s disease —the entorhinal cortex and hippocampus — was able to reverse the loss of connections and to protect from ongoing cell degeneration,” said Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine. “These benefits were observed in aged rats, aged monkeys and amyloid mice.”

Amyloid mice are genetically engineered to inherit a mutation in the gene encoding the amyloid precursor protein. As a result, they develop amyloid plaques, which are aggregates of misfolded proteins in the brain that are considered a hallmark characteristic of Alzheimer’s.

BDNF is normally produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of Alzheimer’s usually appear in the form of short-term memory loss. People with Alzheimer’s have decreased levels of BDNF.

However, BDNF is challenging to work with. It’s a large molecule and cannot pass through the blood-brain barrier. To overcome this issue, researchers will use gene therapy in which a harmless adeno-associated virus (AAV2) is modified to carry the BDNF gene and injected directly into targeted regions of the brain. The team hopes that in these regions, AAV2 will prompt production of therapeutic BDNF in nearby cells.

The injects are precisely controlled to contain exposure to surrounding degenerating neurons since freely circulating BDNF can cause adverse effects like seizures.

The three-year long trial will recruit 12 participants with either diagnosed Alzheimer’s or mild cognitive impairment to receive AAV2-BDNF treatment, with another 12 individuals serving as comparative controls over that period.

This is the first safety and efficacy assessment of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called nerve growth factor (NGF) found heightened growth, axonal sprouting, and activation of functional markers in the brains of participants.

“The BDNF gene therapy trial in AD represents an advance over the earlier NGF trial,” said 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.”

Despite billions of dollars of research investment and decades of effort, there are only two symptomatic treatments for Alzheimer’s. The condition impacts five million Americans and is the sixth leading cause of death in the US. There is no cure or approved way to slow or stop the progression of the disorder.

Many clinical trials are ongoing to assess pharmaceutical treatments. Gene therapy represents a different approach to a disease that requires that requires new ways of thinking about the condition and new attempts at treatments.

“We hope to build on recent successes of gene therapy in other diseases, including a breakthrough success in the treatment of congenital weakness in infants (spinal muscular atrophy) and blindness (Leber Hereditary Optic Neuropathy, a form of retinitis pigmentosa),” Tuszynski said.

“BDNF gene therapy has the potential, unlike other AD 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 AD and MCI.”