First Alzheimer’s gene therapy clinical trial bags $5m

National Institute on Aging awards $5 million grant to UCSD Med School for human clinical trial of gene therapy for treating Alzheimer’s disease or Mild Cognitive Impairment.

The National Institute on Aging (NIA), part of the National Institutes of Health, has awarded a $5 million grant to researchers at University of California San Diego School of Medicine to conduct a first-in-human Phase 1 clinical trial of a gene therapy for treating Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI), a condition that often precedes full-blown dementia.

Longevity.Technology: Gene therapy is an experimental technique that uses genes or gene products to treat or prevent disease instead of relying on drugs or surgery. Research is now building on early gene therapy successes of CAR-T and transgene delivery to refine gene editing and base and prime editing, engineer iPSCs and develop epigenome editing. These next-gen technologies will move gene editing out of the lab and onto the carousel of available and affordable therapies.

The clinical trial, developed by principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, delivers the brain-derived neurotrophic factor (BDNF) gene into the brains of qualifying trial participants where it is hoped it will prompt production of BDNF in nearby cells.

What is brain-derived neurotrophic factor?

BDNF is part of a family of growth factors (proteins) found in the brain and central nervous system that support the survival of existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions susceptible to degeneration in AD.

“We found in earlier studies 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 Tuszynski. “These benefits were observed in aged rats, aged monkeys and amyloid mice [1].”

The three-year-long trial will recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons 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.

Why is this clinical trial important?

“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 [1].”

Tuszynski said the clinical trial has begun enrolling participants; in addition to the NIA funding, the gene therapy trial is supported by a gift of $250,000 from philanthropist Darlene Shiley and a grant of $700,000 from the Alzheimer’s Association.

Researching Alzheimer’s

Brain-derived neurotrophic factor is considered to be a good prospective target for Alzheimer’s research. Previous research has included polymeric nanoparticles that deliver a targeted payload of BDNF; this has shown encouraging results including reversal of cognitive deficits and the targeted delivery means the hurdle of crossing the Blood Brain Barrier (BBB) is avoided.

Curcumin can also boost levels of BDNF, and also serves as a neurotransmitter modulator, helping to maintain neuronal plasticity, which is essential for both learning and memory.

Image courtesy of University of California San Diego School of Medicine