Gene Therapy for Alzheimer's Disease

Harvard Medical School, Boston MA

Investigators

Abstract

PROJECT SUMMARY / ABSTRACT Oxidative damage and inflammation accumulate as we age and are prominent components of many genetic and age-related diseases. Alzheimer?s Disease (AD), and many other neurodegenerative diseases, show signs of oxidative damage and inflammation early in the disease progression. It is likely that the accumulation of a protein, the ?-amyloid precursor protein and its cleavage products, stimulates oxidation and inflammation in AD, beyond an organism?s ability to properly regulate the normally protective responses. Nrf2, a transcription factor, is part of an organism?s normal mechanism to activate a response to abnormal proteins. It regulates >100 genes that can be protective of oxidation, inflammation, xenobiotic stress, and autophagy. However, in AD, it appears that the activity of Nrf2 is not upregulated in response to the disease process. One approach is thus to augment the body?s natural response by delivering the Nrf2 gene using viral gene therapy. This approach has been successful in prolonging vision in animal models of neurodegeneration and acute nerve damage. We propose to test the ability of Nrf2 to reduce the neuronal death and behavioral symptoms in two mouse models of AD. The viral vector, AAV, that will be used for delivery directly to the brain, is being tested as this vector is emerging as a viable candidate for clinical applications. Two mouse models of AD with different genetic causes of AD will be tested to determine if the strategy is applicable across the disease spectrum. In addition, several different assays will be used to test different types of responses as indicators of efficacy. If effective, AAV-Nrf2 may prove to be useful in extending neuronal health and function, not only in AD, but perhaps in other neurodegenerative diseases that also exhibit inflammation and oxidaiton.