Weill Cornell Medicine receives federal grant to study new gene therapy for Alzheimer's disease

The National Institute on Aging of the National Institutes of Health has awarded a five-year grant initially worth $8.37 million for Weill Cornell Medicine researchers to study a new gene therapy for Alzheimer's disease in people who have a high genetic risk of developing the condition. The research could garner nearly $14 million in total if prescribed milestones are reached for years three through five.

The grant will allow researchers to study a treatment for patients with apolipoprotein E4 (APOE4) gene variants inherited from both parents, a group known as APOE4 homozygotes. These people have up to a 15-fold increased risk of developing Alzheimer's, "and it occurs earlier and is more aggressive," said Dr. Ronald G. Crystal, principal investigator and chair of the Department of Genetic Medicine at Weill Cornell Medicine.

For the gene therapy, researchers are combining APOE2, a common variant that protects people from Alzheimer's, with APOE Christchurch, a rare and beneficial variant originally found in a family living in Colombia. People with the APOE Christchurch gene mutation are highly protected from the build-up of protein fragments called amyloid that clump together in the brain to form plaques, and tau protein, which forms tangles and interferes with the brain's function. This protection occurs even in people who have other gene mutations that would normally result in early-onset Alzheimer's disease.

"We thought if we added the APOE2 protective variant to the APOE Christchurch mutation that this would be a super potent protective therapy against APOE4," said Dr. Crystal, who is also the Bruce Webster Professor of Internal Medicine. Preclinical studies of mice with tau buildup and amyloid features of Alzheimer's disease received this combined gene therapy and experienced improved survival and fewer pathological signs of the disease.  

Based on this research, Dr. Crystal and his colleagues will use a modified virus that seeks out the brain to deliver an APOE2 allele engineered to contain the APOE Christchurch mutation in 15 people with early-stage Alzheimer's disease and who are APOE4 homozygotes. This phase 1A trial will assess safety and different doses of the therapy. The researchers will also study early signs of treatment efficacy by measuring levels of APOE2 Christchurch in the cerebrospinal fluid.

A phase 1B study will assess the highest dose tolerated from phase 1A in 10 more people with early-onset disease and inherited APOE4 mutations from both parents. Researchers will conduct brain scans, cognitive tests and biomarker studies to see whether the gene therapy helps reduce signs of Alzheimer's disease.

This research is really a good example of taking a naturally occurring protective mutation found in a unique family, and using that discovery for therapeutic purposes. If we gather enough evidence of efficacy through biomarker measurements, we hope to hand the research over to a company for a larger trial."

Dr. Ronald G. Crystal, principal investigator and chair of the Department of Genetic Medicine, Weill Cornell Medicine