Selective HDAC Inhibition
Although many HDAC inhibitors target cancer, the central nervous system (CNS) represents another lucrative therapeutic domain, notes James Rusche, Ph.D., senior vp, R&D, Repligen. “For example, there are a number of CNS genetic diseases caused by a repetition of a DNA triplet sequence. In Friedreich ataxia (FRDA), a repetitive triplet repeat falls within the first intron of the frataxin gene. This causes hypoacetylation and ultimately blocks normal transcription so that the protein produced is fully functional, there is just not enough of it.”
HDAC inhibitors might provide a new therapeutic strategy for treating FRDA, according to Dr. Rusche. “Research at Scripps showed that one class of HDAC inhibitors could increase the mutant frataxin gene expression. While current HDAC inhibitors for oncology may not work due to toxicity and tissue distribution problems, we felt that we could find better molecules more suited to treating Friedreich ataxia.”
Thus, the company needed to find a more selective HDAC inhibitor that could distribute to brain tissue. “Our preclinical candidate is potent, selective, and possesses the pharmacology needed for an orally active, brain-penetrant drug,” Dr. Rusche reports. “This compound, which is selective for HDAC3, increases expression of the frataxin gene in brain tissue when tested in transgenic mouse models of FRDA at concentrations without side effects. We are now gearing up for clinical trials.”
Other CNS applications that modify histone acetylation will likely follow. “We can envision applications such as Huntington disease, spinal muscular atrophy, and memory modulation. This area of modulating memory is just beginning, but animal studies are providing results that encourage further development in this area.”
Although CNS drug development can be challenging, future HDAC therapeutics are on the horizon. “Most compounds do not get into the brain. The second-generation HDAC inhibitors will likely be much more selective with lowered toxicity and improved delivery to the target tissue. Diseases of the CNS are one important example of how next-generation HDAC inhibitors will provide a much broader opportunity for therapeutics development.