Compound Restores Frataxin Production in FA Cells

Investigators at the Scripps Research Institute in La Jolla, Calif., and the University of California-Los Angeles have identified a chemical compound that can significantly restore levels of a missing protein in cells taken from people with Friedreich’s ataxia (FA).

The work was supported by the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (NIH) and the Friedreich’s Ataxia Research Alliance (FARA), an organization that has recently begun working closely with MDA.

“This compound gets at the fundamental problem in Friedreich’s ataxia,” said Sharon Hesterlee, MDA vice president for Translational Research. “It’s not just a stopgap measure. That’s what’s really exciting about it.”

David Herman and colleagues, whose findings were published online Aug. 20 in the journal Nature Chemical Biology, tried several compounds in a chemical class known as “histone deacetylase (HDAC) inhibitors,” which change the way DNA is packaged in cells. This affects whether genes are switched “on” or “off” with respect to protein production.

Friedreich’s ataxia is a disease that affects the nervous system and heart, leading to severe disability and often to early death from cardiac disease. The underlying genetic defect is almost always an expanded section of repeated DNA sequences on chromosome 9 that affect the gene for frataxin, a protein needed to maintain cellular energy production and normal cellular iron levels.

Working on the hypothesis that the expanded section of so-called GAA repeats causes an abnormal DNA structure and a chemical effect known as “deacetylation” in that section of chromosome 9, the researchers began experimenting with various molecules that they hoped would block deacetylation in that specific area without toxic effects on other chromosomes or on the rest of the cell.

In experiments on white blood cells taken from people with FA, who have a genetic defect in both their two frataxin genes and make very little frataxin, and carriers of FA, who make about 50 percent of the normal level of frataxin and generally have no FA symptoms, they tested the effects of several HDAC inhibitors and zeroed in on one that they’ve dubbed HDAC inhibitor 4b.

This inhibitor, when applied directly to cells in a lab dish, apparently interfered with deacetylation of the frataxin gene region and restored the cells’ ability to read frataxin genes and produce frataxin protein.

In cells from 12 out of 12 FA-affected families, frataxin messenger RNA (a step in protein production after the cell “reads” the DNA code) increased to at least the level seen in untreated carriers’ cells, and frataxin messenger RNA nearly doubled in the carriers.

The researchers say they weren’t sure whether the presence of frataxin RNA would parallel levels of the frataxin protein, but additional experiments showed that cells can make frataxin protein molecules from the newly produced frataxin RNA.

“The next steps are to see whether the molecules act as histone deacetylase inhibitors in animals, whether the molecules increase frataxin messenger RNA and protein in a mouse model for the disease, and whether the molecules are nontoxic to animals,” said Joel Gottesfeld, a professor of molecular biology at Scripps who was on the study team.

“Each of these steps must yield positive results for these molecules to be considered true clinical candidates for FA. Although our results are very encouraging, it will be many months before we know the answers to these important questions.”