Joel Gottesfeld, PhD

Chemical Regulation of Gene Expression. Research in our laboratory is concerned with development of therapeutics for the triplet-repeat neurodegenerative diseases Friedreich's ataxia, myotonic dystrophy and Huntington's disease. The location of these repeated sequences within their resident gene determines whether the disease will be due to epigenetic gene silencing (as in Friedreich's ataxia), RNA toxicity (as in myotonic dystrophy) or a toxic, gain-of-function protein (as in Huntington's disease). Friedreich's ataxia is caused by expansion of a GAA triplet repeat DNA sequence within an intron (a non-coding DNA sequence) of the gene for the essential mitochondrial protein frataxin (FXN). Frataxin is involved in energy production in cells, and loss of this protein leads to the disease. The repeats are known to silence the gene at the level of transcription into messenger RNA by formation of heterochromatin (epigenetic silencing). Since the repeats do not change the coding region of the gene, one therapeutic approach would be to find small molecules that would reactivate this silent gene. We identified a small molecule histone deacetylase inhibitor that is a potent inducer of FXN gene expression and frataxin protein in patient lymphoid cells. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound and a phase I clinical trial in Friedreich's ataxia patients has been performed, with no adverse side effects. Importantly, the FXN gene was activated in lymphocytes taken from the patients, providing a first proof of concept. Further medicinal chemistry efforts have identified improved compounds with superior pharmacological properties for both Friedreich's ataxia and Huntington's disease. With the advent of transcription factor reprogramming of human fibroblasts to induced pluripotent stem cells (iPSCs), we have taken advantage of this technology to derive cellular models for the triplet repeat diseases discussed above. Interestingly, the long repeats in Friedreich's ataxia and myotonic dystrophy iPSCs expand upon derivation and propagation of the iPSCs in culture. This finding has provided a cellular model for repeat instability, where we have implicated the mismatch repair pathway as a major component in repeat expansion. We are also studying the effects of small, DNA-binding pyrrole-imidazole polyamides as modulators of repeat expansion in both Friedreich's ataxia and myotonic dystrophy. Together, our studies point to new therapeutic opportunities for the triplet repeat diseases.