The ultimate goal of this project is to develop an antisense oligonucleotide (AO) therapy for Duchenne muscular dystrophy (DMD). Antisense oligonucleotides (AOs) can be used to reduce the severity of DMD by removing specific exons during pre-mRNA splicing, to either by-pass nonsense mutations or restore the reading frame around dystrophin genomic deletions. As a result of the treatment, dystrophin expression would be restored in dystrophic tissue and DMD patients would theoretically manifest only the milder phenotype of Becker Muscular Dystrophy (BMD). This project will explore the design and delivery of AOs to minimize the consequences of disease-causing dystrophin gene mutations. (1) Animal models of muscular dystrophy will be used to develop treatment regimens and assess therapeutic benefits in vivo. (2) AOs will be designed to target the most amenable splicing motifs at relevant exons in the human dystrophin gene transcript and will be evaluated in cultured human muscle cells. Although this approach cannot permanently correct the primary genetic lesion, we propose that repeated administration, preferably through systemic delivery, should be feasible. AO chemistries or modifications to increase stability and/or uptake, optimized for in vivo induction of exon skipping, will be developed and evaluated. Only periodic administration of AOs should be required to maintain therapeutic levels of induced dystrophin in dystrophic muscle. DMD is a serious disorder for which there is no effective treatment. AOs will not cure this devastating condition, however, AO-based splicing intervention has the potential to reduce the severity of DMD so that treated boys should be able to produce some functional dystrophin. This would be expected to moderate the severity of DMD and improve the quality of life for patients and their families.
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