Abstract
Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few patients surviving beyond their third decade of life as the disease advances and causes cardiac and respiratory difficulties. In recent years, an increasing number of antisense and gene therapies have been studied for the treatment of muscular dystrophy; however, few of these therapies focus on treating mutations arising in the N-terminal encoding region of the dystrophin gene. This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy.
Highlights
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease caused by an inability to produce functional dystrophin, a protein critical for muscular strength and stability, and the absence of which results in progressive muscular deterioration and fibrosis [1–3]
∆Ex3–9 cells showed a restored level of dystrophin production similar to healthy control cardiomyocytes. These findings demonstrate the applicability of exon skipping therapy to treat DMD caused by N-terminal mutations in the dystrophin gene and identify exon 3–9 skipping as a promising and effective therapeutic target
Cohort A recruited six males between 3 months and 3 years of age, while cohort B recruited six males between the ages of 4 and 7 years. Participants in both cohorts are DMD patients with a confirmed mutation between exons 18 and 58 of the dystrophin gene who are otherwise healthy, who test negative for AAVrh74 and AAV8 antibodies, and who have not received any other forms of gene therapy
Summary
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease caused by an inability to produce functional dystrophin, a protein critical for muscular strength and stability, and the absence of which results in progressive muscular deterioration and fibrosis [1–3]. Most DMD patients present with significant lower limb weakness and resulting ambulatory difficulty before the age of 5, progressing to the point of mandatory wheelchair use by age 12 [4] By their late teenage years, most patients suffer from cardiac and respiratory impairment, indicating disease progression to cardiac muscles and the diaphragm. No cure is currently available for DMD, and most existing standards of care aim to delay disease progression through corticosteroid treatment, followed by end-stage ventilatory and cardiac support when the need arises [12,13]. While this approach is often able to extend the life of DMD patients into their mid-to-late twenties, it is far from curative. While AONs generally have a favorable safety profile, the requirement for repeated treatments can add cost and complexity, especially in the setting of chronic disease [16]
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