Featured ScientistsDr. Joel Gottesfeld
Name: Joel Gottesfeld
Where do you work? Scripps Research Institute, La Jolla, California, although I am now retired and my current title is Professor Emeritus.
How long have you been working on FA and who was the first fellow FA researcher you met? My introduction to FA was around 2002, almost 20 years ago. This came about through my position as an Associate Editor of the Journal of Biological Chemistry, where I had the good fortune to review a scientific paper that was authored by Robert Wells and his colleagues, including our colleague Marek Napierala. Work from Bob Wells’ laboratory in Houston showed that the primary genetic mutation that causes FA, expansion of the GAA repeats in the frataxin gene, causes the DNA to adopt an unusual structure which they called “sticky” DNA. They hypothesized that sticky DNA prevents the enzyme RNA polymerase from copying the frataxin gene into messenger RNA, thereby reducing the amount of frataxin protein in patient cells. They concluded their paper by speculating that a small molecule that would drive sticky DNA back to normal DNA could reactivate the frataxin gene and serve as a therapy for the disease. I was really taken by this paper and the possibility that I could contribute to FA research and drug development.
What got you interested in FA research? Since my lab worked on small molecules that can be designed to bind DNA of virtually any sequence, it was immediately clear to me that we might be able to make a contribution to FA by designing and synthesizing such a molecule. My colleague Christian Melander, who was a postdoc in the lab at the time, set about making a series of molecules, called pyrrole-imidazole polyamides, to bind the GAA repeats. We were successful and this work was published in the journal Proceedings of the National Academy of Sciences in 2006. However, the molecules that we had at the time did not enter the central nervous system and hence we sought different approaches to FA therapeutics.
What question or challenge were you setting out to address when you started this work? To develop therapeutics for FA we needed to know just how the GAA repeats silence expression of the frataxin gene, so we set out to figure out in molecular terms just what the mechanism of gene silencing might be. Since I had a background in studying how chromosomal proteins affect gene expression, my feeling was that DNA structure was not the only thing going on and the chromosome environment of the gene might also be an important determinant. I had the good fortune to have Elisabetta Soragni join the lab at the time, and she had previous experience in using a technique called ChIP, which allows scientists to probe the proteins that are associated with any gene in cells. We believed that modifications of the histone proteins that bind DNA might be responsible for turning off the frataxin gene in response to the GAA repeats. This turned out to be the case, and Liz was able to show that the histone proteins associated with the frataxin gene had all the hallmarks of silent genes. This led to our hypothesis that small molecules that act on these histone signals might reverse silencing. Indeed, we found that a specific class of molecules called histone deacetylase or HDAC inhibitors reversed silencing. In collaboration with Massimo Pandolfo’s lab (Brussels, Belgium) and Mark Pook’s lab (London, UK) it was shown that these molecules are active in two FA mouse models. At this point we collaborated with a biopharmaceutical company called Repligen. Repligen synthesized a series of derivatives of our original molecule and identified a clinical candidate called RG2833. A small clinical trial in FA patients was conducted in 2012. RG2833 was shown to be active in circulating white blood cells in FA patients but unexpected problems were identified. To circumvent these issues, this technology was passed onto BioMarin Pharmaceutical in 2014, but unfortunately, BioMarin has recently decided not to pursue this technology further.
Name: R. Mark Payne 
Name: David Lynch, MD, PhD 
Name: Myriam Rai 
Name: Dr. Marek Napierala 
