Muscular dystrophies are genetic disorders characterized by muscle regenerative deficits, extensive muscle loss and fibrosis. One such disease, Duchenne muscular dystrophy (DMD), is a severe and relentlessly progressive myopathy that results from mutations in the X-linked DMD gene that disrupt the mRNA reading frame and prevent translation of the muscle structural protein, dystrophin. In DMD, the lack of dystrophin leads to chronic muscle degeneration, inflammation and fibrosis, resulting in a loss of muscle structural integrity and myofiber death. A promising genetic therapeutic strategy for DMD and other neuromuscular diseases is 'exon skipping' through the use of antisense oligonucleotides (AOs). This class of drug allows for ‘exon skipping’ of the mutated exons in the patient’s dystrophin gene to restore a functional, truncated dystrophin protein, and is currently the only approved genetic therapy for the treatment of DMD. A major focus of our research investigates how the complex pathological processes in DMD and muscular dystrophies modulate the delivery and therapeutic efficacy of antisense chemistries and gene therapies to develop novel delivery strategies to improve the pharmacokinetics and efficacy of these therapeutic agents for muscle diseases.
In addition, we are focused on unraveling the complex and aberrant cellular and molecular processes that contribute to disease onset and progression in DMD. Skeletal and cardiac muscle function in DMD patients progressively worsens due to muscle atrophy, inflammation, fibrosis, and cell death, which ultimately leads to skeletal and cardiac muscle dysfunction and failure. Fibrosis can contribute to cardiac dysfunction in DMD patients as early as 7 years of age and cardiomyopathy and heart failure are the leading causes of death in DMD patients. A variety of therapeutic strategies have aimed to modulate inflammatory and fibrotic pathways for DMD, but this task is complicated as these are critical processes that function in both normal tissue repair and aspects of DMD disease pathogenesis. The major goals of our work here are to identify and test novel therapeutic targets aimed to combat these secondary pathologies, including fibrosis, inflammation and muscle degeneration to improve skeletal and cardiac muscle function and the quality of life for patients living with muscular dystrophy.