What patients and families need to know
The Children's National Research Institute
In our laboratory, we are focused on investigating the cellular and molecular mechanisms that regulate the delivery and efficacy of 'exon skipping' antisense oligonucleotide chemistries in order to further optimize this approach for Duchenne Muscular Dystrophy. We believe that investigation of how satellite cell-mediated growth and repair, as well as disease pathology, influences drug delivery and efficacy will lead to identification of novel therapeutic targets and improved clinical outcomes for Duchenne.
Antisense Oligonucleotide Delivery
Exon skipping is a promising therapeutic strategy for Duchenne Muscular Dystrophy, which utilizes antisense oligonucleotides to exclude mutated exons from the DMD mRNA transcript and elicit production of truncated dystrophin protein. Both preclinical and clinical trials for the leading antisense candidates have shown limited and variable dystrophin rescue, leading to questions surrounding the efficiency of delivery into muscle fibers. Our current research focuses on defining the mechanisms of delivery for different antisense oligonucleotide chemistries into muscle fibers, and investigating how different stages of disease pathogenesis influences drug pharmacokinetics and pharmacodynamics and efficiency of exon skipping.
Duchenne Pathology and Muscle Repair
The pathology of Duchenne Muscular Dystrophy is characterized by chronic inflammation and persistent muscle degeneration and regeneration, which ultimately lead to a loss of muscle structural integrity and functional strength. It has been demonstrated that the phenotypic variability observed in dystrophic mouse models can be partly attributed to genetic modifiers that modulate disease processes and severity. Currently, we are investigating how genetic modifiers modulate muscle growth and repair in the context of varying disease pathology to better characterize the function of myogenic precursor cells (satellite cells) through stages of muscle growth and disease pathogenesis.