Histone Deacetlylase Inhibitors May Hold Cure for Friedreich Ataxia

A team from the The Scripps Research Institute (TSRI) was able to reactivate a gene, the metabolic silencing of which is responsible for Friedreich ataxia, a rare autosomal recessive neurodegenerative disorder that leaves affected persons crippled and vulnerable to scoliosis, diabetes, and heart disease. The research team, led by Joel Gottesfeld, PhD, a professor in the Department of Molecular Biology at TSRI in La Jolla, California, set about identifying and testing compounds that inhibited histone deacetylases in lymphocytes from persons with Friedreich ataxia. They hit upon one-BML-210-that reactivated the frataxin gene.

In Friedreich ataxia, frataxin gene and protein expression is squelched by abnormally voluminous GAATTC trinucleotide repeats within intron 1 of the gene. Mitochondrial dysfunction ensues. Although patients-typically pediatric-are managed with surgery and orthotics, morbidity is high and death is premature. Clinical research has focused on interruption of the GAATTC repeats.

Drawing on the "histone code" theory, which posits that histones require certain components-such as acetylases-to allow nucleosomes to form properly so that genes can express themselves, the TSRI team confirmed that certain irregularities in histones, namely deacetylation and subsequent heterochromatin formation, were associated with frataxin silencing. They went on to show that BML-210 reversed heterochromatin formation in cultured lymphocytes and somewhat increased frataxin mRNA. The researchers then chemically modified BML-210, producing a series of analogs. One class caused an increase in frataxin transcription such that the gene was consistently reactivated in all cells tested.

The researchers, as well as Ron Bartek-president of the Friedreich's Ataxia Research Alliance, which funded the study with the National Institute of Neurological Disorders and Stroke-lauded the findings as a significant breakthrough in the management of this disease. The histone deacetylase inhibitors used in the research have proved to be nontoxic in animal studies so far. If the results of animal studies remain positive, Gottesfeld said that clinical trials may be as soon as 18 months away.The current citation for this study is Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol. 2006;2:551-558.