Research in our laboratory is concerned with furthering our
understanding of the molecular basis for several human diseases,
including the neurodegenerative and neuromuscular diseases :
Friedreich’s ataxia
Huntington’s disease
Spinal muscular atrophy. 
Our efforts are also aimed at development of novel therapeutic
approaches for these diseases. 

 

Numerous studies have pointed to histone deacetylase (HDAC) inhibitors as potential therapeutics for various neurological and neurodegenerative diseases, and clinical trials with several HDAC
inhibitors have been performed or are underway. 
However, the HDAC inhibitors that have been tested
to date are either highly cytotoxic or have very low
specificities for different HDAC enzymes. In the course of studies on
Friedreich’s ataxia (FRDA),our laboratory identified a novel class of
HDAC inhibitors (pimelic o-aminobenzamides) that reverse
heterochromatin-mediated silencing of the frataxin (FXN) gene in this
disease. Our studies show that these HDAC inhibitors cross the blood brain
barrier in mice, exhibit no acute or chronic toxicity at potential therapeutic
doses, and act as HDAC inhibitors in the mouse brain. Importantly, our compounds increase FXN mRNA levels in the brain and heart in a mouse model for FRDA. We have also derived a human neuronal cell model for FRDA based on differentiation of patient-derived induced pluripotent stem cells. These cells retain FXN gene silencing, exhibit repeat expansions as in the human disease, and respond to the HDAC inhibitors, yielding therapeutically beneficial levels of FXN gene expression. Compound libraries have been generated and screened for activity in the various cellular and mouse models and a clinical candidate has been identified and subjected to full pharmacological and toxicology testing. An Investigational New Drug application has been submitted to the US Food and Drug Administration and phase I clinical trials should commence shortly. Similar efforts in Huntington’s disease and spinal muscular atrophy will hopefully lead to similar therapeutic approaches.