The National Institutes of Health’s National Institute on Aging has awarded a five-year grant worth an initial $8.37 million to Weill Cornell Medicine researchers studying new gene therapies for people at high genetic risk of developing Alzheimer’s disease. If certain milestones are reached between years three and five, the study could earn a total of nearly $14 million.
The grant will enable researchers to study treatments for patients with inherited apolipoprotein E4 (APOE4) gene mutations from their parents, a group known as APOE4 homozygotes. These people are up to 15 times more likely to develop Alzheimer’s disease, and “Alzheimer’s disease occurs earlier and is more aggressive,” said Dr. Ronald G. Crystal, principal investigator and chief of genetics at Weill Cornell Medicine.
For the gene therapy, researchers are combining APOE2, a common variant that protects people from Alzheimer’s disease, 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 buildup of protein fragments called amyloid, which clump together to form plaques in the brain, and the tau protein, which forms tangles and interferes with brain function. This protection also occurs in people who have other genetic mutations that would normally cause them to develop Alzheimer’s disease earlier.
“We thought that if we added the APOE2 protective variant to the APOE Christchurch mutation, we would have a very powerful protective therapy against APOE4,” said Dr. Crystal, who is also the Bruce Webster Professor of Internal Medicine. Preclinical studies of mice with tau accumulation and amyloid hallmarks of Alzheimer’s disease showed improved survival and decreased pathological signs of the disease after receiving this combined gene therapy.
Building on this study, Dr. Crystal and his colleagues plan to use a brain-seeking engineered virus to deliver an APOE2 allele engineered to contain the APOE Christchurch mutation to 15 early-stage Alzheimer’s patients who are homozygous for APOE4. This Phase 1A study will evaluate the safety of the treatment and different doses. The researchers also plan to study early signs of treatment efficacy by measuring APOE2 Christchurch levels in cerebrospinal fluid.
The Phase 1B study will evaluate the highest dose tolerated in Phase 1A in 10 additional patients with early-onset disease who inherited the APOE4 mutation from their parents. Researchers plan to conduct brain scans, cognitive tests and biomarker studies to see if gene therapy can help reduce symptoms of Alzheimer’s disease.
This study is a really good example of taking a naturally occurring protective mutation found in a unique family and using that discovery for therapeutic purposes. If we can gather enough evidence of efficacy through biomarker measurements, we hope to hand over the research to a company to conduct large-scale trials. ”
Dr. Ronald G. Crystal, principal investigator and chief of genetics at Weill Cornell Medicine
