KYLE BRYANT TRANSLATIONAL RESEARCH AwardS

James R. Rusche, PhD

Repligen Corporation
Development of Methods to Determine the Pharmacodynamic Effect of HDAC Inhibitors on Frataxin Expression

The development of new treatments for Friedreich’s ataxia include treating symptoms caused by the genetic mutation in the frataxin gene or reversing the low expression of the gene frataxin. The restoration of the frataxin protein levels is an approach meant to modify the course of Friedreich’s ataxia. Recent studies have suggested compounds that change the chromatin covering the frataxin gene can result in raising the amount of frataxin protein. This observation has been shown in primary cultures of patient cells as well as a transgenic mouse model containing a triplet repeat expansion within the frataxin gene similar to that seen in patients. While these are promising observations, the use of HDAC inhibitors chronically in patients requires methods to monitor the effect of a specific treatment on the frataxin gene to help guide what dose of drug to use and how often to take the drug in order to get the maximum positive effects with the least toxicities.

The objective of this grant is to use model HDAC inhibitors to create a standard measure of compound effects on frataxin gene expression. The studies will establish quantitative measures of drug in brain tissue of transgenic mice and correlate that to the amount necessary to get
more frataxin protein. These techniques can then be used to identify the best compound for testing in man. These methods, once defined, can form the foundation for measures performed as part of future clinical trials.