David G. Morgan, Ph.D.

Anti-Amyloid Gene Therapy for Alzheimer's Disease

The accumulation of Abeta peptide, resulting from the cleavage of the amyloid precursor protein (APP) by the joint actions of beta secretase and gamma secretase, is thought to be a precipitating factor in Alzheimer's disease. Many proposed strategies for treating Alzheimer's disease have focused upon lowering the production of Abeta or enhancing its clearance from the brain. We propose here a relatively new approach to lowering brain Abeta by exploiting a gene therapy approach.

This proposal unites our expertise to develop viral vectors for gene therapy applications with the expertise in evaluating amyloid lowering therapies in transgenic mouse models of amyloid deposition. The outcome of these studies will, hopefully, be a novel gene therapeutic approach for the treatment and cure of Alzheimer's disease. Specifically we will test adeno-associated viral (MV) vectors which have a remarkable record for safety in both mice and humans. We will compare, a) vectors that are designed to produce enzymes that degrade the Abeta peptides with b) vectors designed to block the activity of the enzymes which produce the Abeta peptide using an RNA interference approach. A priori, we cannot predict which of these approaches might have the greatest efficacy in lowering Abeta or the greatest margin of safety for human clinical trials.