Phase 1 Trial to Test BDNF Gene Therapy in Alzheimer’s Patients

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A Phase 1 trial will evaluate the use of gene therapy in delivering brain-derived neurotrophic factor (BDNF) to the brains of people with Alzheimer’s disease or mild cognitive impairment (MCI), which often precedes dementia.

Researchers at the University of California San Diego (UCSD) School of Medicine are preparing to open a three-year trial in 12 people diagnosed with either with Alzheimer’s or MCI, according to a university press release. The release did not specify if eligible patients need to be at particular stages of Alzheimer’s.

The trial will assess the safety and efficacy of injecting the BDNF gene, carried on an engineered adeno-associated virus (AAV2), directly to certain brain regions in these 12 patients.

Another 12 people will serve as an untreated control group for comparison.

BDNF is a neurotrophin, a protein that promotes the growth and survival of both new and existing neurons. The protein also functions as a neurotransmitter, mediating communication between nerve cells.

It is active in several brain regions susceptible to degeneration over the course of Alzheimer’s. Past research has identified mutations in the BDNF gene that impair its signaling ability, and which associate with faster cognitive decline and a higher risk of developing Alzheimer’s.

The research team conducting the trial previously found that BDNF could prevent and reverse brain cell degeneration and death in rat, monkey, and mouse models of Alzheimer’s.

“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, senior author of a 2009 study of this preclinical work.

The entorhinal cortex produces BDNF and functions as a hub for memory, navigation, and the perception of time. Although it normally produces BDNF throughout a person’s life, people with Alzheimer’s tend to produce less of it.

The investigators plan to deliver the BDNF gene to patients via AAV2 because the BDNF protein is too large to cross the blood-brain barrier. The injections will be targeted to specific brain areas, as too much freely circulating BDNF can cause harmful side effects such as seizures.

UCSD has participated in past Alzheimer’s gene therapy trials, which used an AAV vector to deliver a different neurotrophin named nerve growth factor (NGF) to the brain. The university reports that data from one past trial showed increased nerve growth, the formation of new nerve connections, and activation of functional markers in participants’ brains.

Tuszynski believes that therapeutic BDNF represents an improvement over trials using NGF.

“BDNF is a more potent growth factor than NGF for neural circuits that degenerate in [Alzheimer’s],” he said. “In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

The upcoming trial will be the first to evaluate the use of AAV2–BDNF in humans.

“BDNF gene therapy has the potential, unlike other [Alzheimer’s] therapies currently under development, to rebuild brain circuits, slow cell loss and stimulate cell function,” Tuszynski said. “We are looking forward to observing the effects of this new effort in patients with [Alzheimer’s] and MCI.”

Anyone wanting more information on this Phase 1 trial can contact Michelle Mendoza at 858-822-7438 or by sending an email to [email protected].

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