Identifying Novel Therapeutics and Therapeutic Entry Points for the Treatment of Duchenne Muscular Dystrophy Through Regulation of Gene Expression

Abstract

My graduate research has primarily focused on genetic and epigenetic modifiers of Duchenne muscular dystrophy and understanding how those modifiers can be used as novel therapeutic entry points for treatment. A vast array of promising therapeutic strategies is being explored outside the realm of directly targeting dystrophin deficiency. This is primarily due to the lack of successful clinical trials that have demonstrated the ability to benefit a significant number of DMD patients. Here, I have expanded the field’s understanding of using the regulation of gene expression as a way to target dystrophin-deficiency associated pathology through, 1) therapeutic treatment of a DMD mouse model using a novel SINE (Selective Inhibitor of Nuclear Export) compound, and 2) characterization of the role of a muscle-enriched microRNA, miR-486, in disease progression. I have demonstrated that inflammation-related DMD pathology can be subdued through indirect inhibition of the expression of inflammation-related genes via SINE compound KPT-350. In addition, I have uncovered novel targets of miR-486, which may be promising and viable targets for therapeutic intervention. Collectively, my studies on these modulators of gene expression have contributed to deepening the field’s understanding of potential avenues for uncovering promising therapeutic targets for DMD pathology.