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Featured Scientists

Every few months, FARA will introduce one of our researchers to you.

Feature articles include their area of research, the focus of their work and how they are helping us to achieve our goal- an effective therapy, and eventually a cure for FA.


 

Dr. Joel Gottesfeld

David Lynch 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.

David LynchWhat 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.

Dr. Mark Payne

Myriam-Rai 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).

David Lynch

David Lynch 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.

Myriam Rai

Myriam-Rai Name: Myriam Rai

Title: PhD Since 2002, I have been working at the Experimental Neurology Laboratory at the Université Libre de Bruxelles (ULB) in Brussels, Belgium. I am currently starting my new job with FARA as a Director of Global Relations and Initiatives.

What got you interested in FA research? My journey in FA started with Massimo Pandalfo. After spending an hour in his office, I remember leaving with the original reprint of the Science paper describing the GAA repeat expansion in FA. The next morning I decided to go for a PhD on FA. I was quickly introduced to the FA community: scientists, clinicians, advocacies, and of course persons living with FA.

What do you see as your primary responsibility as the Director of Global Relations & Initiatives? I was always impressed by FARA’s work: the scientific conferences, the fundraising activities, the grant management… When Jen Farmer and I discussed the opportunity to work together for a global approach towards a cure for FA I realized the challenge to putting together more synergy but overall, its value. My primary responsibility will be developing relationships with non-US key stakeholders: scientists, clinicians, pharmaceutical and biotechnology companies, patient advocacy organizations and government agencies. I hope to help to advance FARA’s research priorities on a global scale and accelerate research towards a cure for FA.

Marek Napierala

marek-napierala Name: Dr. Marek Napierala

Where do you work? My laboratory is located at the University of Alabama at Birmingham, Department of Biochemistry and Molecular Genetics.

How long have you been working on FA and who was the first fellow FA researcher you met? I have been working on repeat expansion diseases for the past ~ 25 years and focusing on FA for the past 18 years. The first researcher I met in the field was Dr. Robert D. Wells, who then was heading the Center of Genome Research Institute of Biosciences and Technology Texas A&M University in Houston. He was working on various repeat sequences, including GAA repeats. At the time (1995), we did not know that these repeats are expanded in the FXN gene in people with FA.

What got you interested in FA research? I was interested in repetitive DNA elements even prior to the discovery that expanded GAA repeats are the mutation causing FA. The mechanism of how unstable repeat sequences expand from a few repeats to hundreds and even thousands intrigued me when I was a graduate student and during my early career as a postdoc. Then, this interest evolved into a fascination with understanding the connection between expanded DNA and decreased frataxin expression (i.e. mechanism of epigenetic silencing). This was certainly influenced by a collaboration between my mentor at the time (Dr. Wells) and Dr. Joel Gottesfeld (Scrippts Institute), whose group discovered and defined epigenetic changes at the FXN gene.

What question or challenge were you setting out to address when you started this work? When I started as a postdoc working on FA, we did not know the mechanism causing the transcriptional block in FA. We knew that the atypical DNA shape adopted by long GAA repeats was a part of it, but we also suspected that this was not the only reason. We were, and still are, puzzled by the unusual properties of these repetitive DNA sequences that enable them to grow (i.e. increase number of repeats).

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