Inhibitors of Excision Repair as a Therapeutic to Prevent DNA Amplification Events

Reference #:

2004-284

Inventors/Contributors

Cynthia T. McMurray, Ph.D.

Description

We have found that onset of neuronal toxicity in HD (Huntington's) may arise from cellular expansion of simple repeating DNA sequences due to an excision process normally meant to correct DNA. Loss of a single base excision repair enzyme, 8-oxo-guanine glycosylase (OGG1), in mhtt expressing animals stops the expansion mutation of CAG triplet repeats. Loss of expansion was accompanied by an unforeseen amelioration (or at least a substantial delay) of pathophysiology in a mouse model for neurodegeneration. Animals containing a disease gene but missing OGG1 lacked visible signs of disease typically observed late in the lifetime of these animals (in contrast to their normal littermates). These data demonstrate, for the first time, the unexpected finding that excision and removal of damaged DNA is causative for both DNA expansion and the onset of toxicity. If excision of damaged DNA can cause mutation and toxicity at particular sites in the genome, then inhibition of excision should be therapeutic against DNA amplification and related diseases.

Patent Status

Pending