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.
What research topics or questions are you currently focused on? While I am now retired from active research, I still believe that the HDAC inhibitors have promise as a therapy for FA. So, my efforts are directed toward finding a new home for the HDAC inhibitors, ideally in an existing company that has expertise in drug development for rare diseases.
What do you hope to achieve or what excites you in FA research? What really excites me right now is the achievement our colleague Aseem Ansari has made in modifying our original polyamide targeting the GAA repeats. Aseem attached another small molecule that has been shown to target other gene regulatory proteins to our original molecule FA1 and showed that the new molecule (called Syn-TEF1 for synthetic transcription elongation factor 1) has much greater activity than our original molecule. Moreover, Aseem and colleagues showed that the molecule works in FA neuronal cells and in a mouse. A new company called Design Therapeutics is now taking this class of molecules forward as therapeutics for FA. I would be thrilled if our work from several years ago actually contributed in a small way to a therapy for the disease. This is a truly exciting time in FA research as numerous excellent laboratories and pharmaceutical companies are making great progress toward treatments.
If you have met someone living with FA, please tell us about that interaction. Did it have an impact on your work? I have met numerous individuals with FA and I know parents who have lost children to the disease. Knowing patients and family members has been a true inspiration for me. These interactions provide purpose to our work and show the urgency of finding treatments.
You serve voluntarily on FARA’s Scientific Advisory Board. Please tell us what you see as FARA’s key role in the research process. I am glad to be a member of the Scientific Advisory Board for FARA and I am pleased to participate in zoom conferences and grant reviewing for FARA. Hopefully in-person meeting will take place in the near future. FARA has been a tremendous resource for my previous research efforts. FARA provided numerous grant awards to my lab at Scripps and without their support we would not be where we are today. So, thank you to FARA and to all of the individuals who has contributed both financial resources and effort to this phenomenal organization. What I tell other scientists outside of the FA field is that FA research is unlike any other disease specific field due to FARA and their commitment to fostering a collaborative and exciting research environment.