Name: Kevin Whittlesey

Where do you work? 4D Molecular Therapeutics; Emeryville, CA.

How long have you been working on FA and who was the first fellow FA researcher you met? I first interacted with FARA about 4 years ago. The staff at FARA (specifically Jen Farmer and Jane Larkindale) were incredibly helpful at providing insight into the current state of research in FA and how best to help meet the needs of people living with FA.

What got you interested in FA research? There is tremendous unmet medical need in FA which presents a significant opportunity for gene therapies to help people living with FA.

What question or challenge were you setting out to address when you started this work? 4D Molecular Therapeutics is a gene therapy company using a Therapeutic Vector Evolution process to identify and select gene therapy viral vectors that are targeted to particular tissues in the body to improve outcomes for the people living with genetic conditions.

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

Title: MD Indiana University School of Medicine, Dept. of Pediatrics, Division of Pediatric Cardiology, Wells Center for Pediatric Research, Indianapolis, IN.

How long have you been working on FA and who was the first fellow FA researcher you met? I‘ve been working on FA since about 2001, when I was faculty at Wake Forest Univ. School of Medicine. Ron Bartek was the first person from FARA that I met when he came down to meet me at Wake Forest. He helped me get started in FA, introduced me to FARA and helped me win a FARA seed grant, and introduced me to Helene Puccio. Helene graciously shared her FA mice with me to let me test a drug for FA. As a result of this support, I changed the direction of my research to focus on FA and I have remained in the field ever since.

What got you interested in FA research? It was a result of my earlier training. During my postdoctoral work as part of my pediatric cardiology fellowship at Washington University in St Louis, I became interested in how proteins target and are imported into mitochondria. The lab that I trained in was directed by a pediatric cardiologist, and this influenced my research career. He had a focus on how mitochondrial dysfunction caused sudden infant death in young children. As a cardiologist I was interested in how defective mitochondrial function contributed to poor heart function in children with heart disease (cardiomyopathies).

Name: David Lynch, MD, PhD

Title: Professor of Neurology at Children's Hospital of Philadelphia / University of Pennsylvania

When did you first start working on FA and where do you work currently? A word I sometimes use to describe how I got into this: destiny. Over time, it seems like this was what I was supposed to do. I first started working on FA 25 years ago when I met Rob Wilson. Currently, I work at the Children’s Hospital of Philadelphia (CHOP) and at the Center of Excellence (COE) at the University of Pennsylvania.

What got you interested in FA research? Rob had a small clinical FA project that he needed a neurologist for, and Kurt Fischbeck suggested me.

What question or challenge were you setting out to address when you started this work? We were interested in finding out the underlying pathobiology of FA.