The Impact of microRNAs on Dystrophin Rescue and Disease Progression in Duchenne Muscular Dystrophy
Abstract
Duchenne Muscular Dystrophy Research Program (DMDRP) Focus Area: The Focus Area that aligns with my proposed work is “Expansion of existing preclinical translational data in support of a specific therapeutic development path.” The aims proposed in my DMDRP Career Development Award application will build on existing data from Duchenne muscular dystrophy (DMD) exon skipping studies and explore how blocking microRNAs could serve as a potential therapy for DMD either alone or in combination with exon skipping drugs. Career Goals: I am a senior postdoctoral fellow at Children’s National Medical Center who has specific expertise in molecular biology, signal transduction, muscle pathophysiology, and genetics. I am currently at the transition stage between trainee and faculty within my career, and the DMDRP Career Development Award would serve as an important stepping stone in my career development path. My career goals are simple: I want to continue (1) researching the basic science underlying DMD and Becker muscular dystrophy (BMD) and (2) pursuing therapies to treat DMD. I am extremely passionate about and connected to this work because of my personal experiences volunteering with the Muscular Dystrophy Association Camps. In order to achieve my research and career goals, I need protected time to develop new tools, obtain new training, and differentiate my own independent research program. As a faculty member, I will be fully committed to pursuing DMD research as well as participating in DMD patient advocacy, outreach, and public policy. Applicability of the Research: Cutting-edge precision medicine drugs that act through a mechanism known as exon skipping are currently in clinical trials for DMD. These drugs act through a mechanism which partially “rescues” dystrophin, the protein that is deficient in DMD. To date, one of the major challenges with DMD exon skipping trials is inconsistency and unevenness of rescued dystrophin; this has been a significant and critical barrier to obtaining new drug approval. Highlighting this, on April 25th a Food and Drug Administration (FDA) advisory panel voted against accelerated approval of the most promising exon skipping drug, eteplirsen, due to low and inconsistent dystrophin rescue in a Phase IIb clinical trial. On September 19th, after much debate, the FDA granted accelerated approval to eteplirsen. The accelerated approval granted by the FDA, however, is conditional. Full approval will rely on a confirmatory clinical trial in DMD boys that unequivocally shows efficient dystrophin rescue. Collectively, these events emphasize the urgent need to understand the causes of variable and low dystrophin rescue in exon skipping. Recently, we discovered that a small, non-coding RNA called microRNA 146a (miR-146a) is significantly higher in DMD muscle than in healthy muscle. miR-146a increases as DMD disease worsens, and its expression is tightly linked with inflammation. We also found that miR-146a directly blocks dystrophin protein production and its high expression in DMD muscle prevents successful dystrophin rescue via exon skipping drugs. Work proposed in this application will test the hypothesis that miR-146a is detrimental to DMD disease course and that blocking miR-146a in combination with exon skipping will improve the amount of rescued dystrophin to help treat DMD. The major goals of this work are to better understand how miR-146a effects DMD disease progression and inflammation and to move towards preclinical development of miR-146a “blocking” agents, as we have a pending patent to therapeutically target miR-146a and other microRNAs in both in BMD and DMD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710475
Entities
People
- Alyson A Fiorillo
Organizations
- United States Army