2023 Alzheimer's Association Research Grant (AARG)

Combined Lecanemab Immunotherapy and BDNF Gene Therapy for AD

Can a combination of therapies that target the health of nerve cells and the accumulation of beta-amyloid protein delay the onset of Alzheimer’s?

Michael J. Castle, Ph.D.
University of California, San Diego
San Diego , CA - United States

Background

Beta-amyloid is a sticky protein fragment that forms abnormal clumps called plaques in the brain, a key hallmark of Alzheimer’s. Researchers have developed antibody therapies that use the body’s own immune system to target and remove beta-amyloid plaques. Lecanemab is an amyloid immunotherapy (antibody) that has shown beta-amyloid-clearing abilities in clinical trials and has been approved by the FDA. However, it has only modest effects on slowing cognitive decline. 

Dr. Michael Castle and colleagues believe that Lecanemab’s efficacy may be improved by combining it with an approach that targets a distinct biological pathway. BDNF (brain-derived neurotrophic factor) is a protein that occurs naturally in the brain and is essential for the health and survival of nerve cells. It has been challenging to develop BDNF as a drug therapy because it does not enter the brain from the bloodstream. Dr. Castle and colleagues have been developing a novel technique for delivering a gene therapy for BDNF gene directly into the brain. This gene therapy technique requires only a single injection and leads to prolonged increases in brain BDNF levels. This mechanism differs from many other treatments being developed for Alzheimer’s because it targets the survival of nerve cells rather than the removal of beta-amyloid plaques and tau tangles (another hallmark brain change in Alzheimer’s) from the brain.

Research Plan

Dr. Castle and team will study the effectiveness of Lecanemab immunotherapy and BDNF gene therapy individually and in combination in genetically engineered Alzheimer’s-like mice. After treatment, the researchers will conduct behavioral tests to evaluate cognition and RNA sequencing to better understand the biological mechanisms underlying the treatments’ effects.

Impact

This project will add to the understanding of two promising therapeutics for Alzheimer’s and may potentially identify a new combination therapy to evaluate in future clinical trials.