Sanjay Bidichandani, MBBS, PhD, professor of Pediatrics at the University of Oklahoma Health Sciences Center, has an ongoing MDA research grant (totaling $300,000 over three years) to study the role of epigenetic silencing of the frataxin gene (FXN) in Friedreich’s ataxia (FA). (Epigenetic changes to the genome are factors that influence the activity of genes but do not change the basic coding, or DNA sequence, of a gene.)
In FA, mutations in the FXN gene cause decreased production of frataxin protein, resulting in diminished energy production in cells, including those of the nervous system and heart. In past work, Dr. Bidichandani discovered a DNA hypermethylation in FXN of people with FA. (In the case of hypermethylation, there is an increase in a specific chemical tag on certain molecules of the DNA sequence.) However, to identify effective therapeutic targets and biomarkers, a complete understanding of exactly how the silencing mechanism works is needed.
In this project, Dr. Bidichandani will look more closely at the two main mechanisms of FXN gene silencing to see if one mechanism precedes the other, or if they work in parallel. This information will reveal whether different therapeutic agents can work synergistically or limit the effectiveness of each other.
Please describe your current research.
This is a basic research project. We recently discovered a unique epigenetic signal called DNA hypermethylation in the FXN genes of people with FA. Our project is designed to test the hypothesis that this particular epigenetic signal acts as a barrier to efficient gene reactivation in FA. Using state-of-the-art tools, we will test this hypothesis in cells from people with FA and in a humanized mouse model.
What is the focus of your research in FA, and why is it important?
People with FA produce very little frataxin protein because of a unique mutational mechanism. The downstream consequences of this deficiency result in the clinical manifestations of FA. My lab is dedicated to understanding the precise mechanism of gene silencing in FA so that we may be able to turn it back on as a therapeutic strategy.
What inspired you to study FA?
I have been involved in FA research since I was a postdoctoral fellow, when I was supported by a postdoctoral fellowship from the MDA (1995-1997). MDA’s funding was critical in the discovery of the FXN gene, which I was privileged to be involved in, and since then I have remained in FA research.
What is the expected outcome of your research?
This work will help us design more effective strategies to reactivate the silenced FXN gene in FA.
How will your research lead to treatments and cures?
The mechanism of gene silencing in FA is known as epigenetic silencing. As we dig deeper, we realize that the silencing mechanism is more complex than was initially appreciated. A fuller understanding of the epigenetic silencing mechanism will help yield therapeutic targets and perhaps even biomarkers to track therapeutic response in people with FA.
Why is it important that MDA continue to fund research in FA?
FA is a devastating condition, and there are no effective therapies to stop or slow its relentless progression. We are thankful to MDA and its supporters/donors for continuing to fund research in FA. MDA’s continued support is a source of much hope for the FA community.