LGMD R2(2B)

J Vis Exp. 2018; (131): 56999.

Limb-girdle muscular dystrophy 2B (LGMD2B, also known as LGMD R2), Miyoshi myopathy (MM), and distal myopathy of the anterior tibialis (DMAT) are rare autosomal recessive forms of muscular dystrophy all caused by dysferlin deficiency. These are collectively called dysferlinopathy.

Recently, my research team and another group have pointed out that antisense-mediated exon-skipping therapy is potentially applicable to LGMD2B, MM, and DMAT. Some patients with large deletions in the DYSF gene have been reported to show relatively mild phenotypes, suggesting that internally deleted dysferlin proteins can be functional. The goal of exon-skipping is to deliver antisense oligonucleotides (AONs) targeting a specific exon (or exons) of the mutated gene. The antisense drugs are designed to bind the complementary sequence in the pre-mRNA. The AONs block inclusion of the mutated exon, or neighbouring exon(s) in the RNA splicing process. The exclusion of these exon(s) restores the reading frame of the mRNA transcript, thereby enabling the production of truncated but partially functional protein. Recent research from my group showed that antisense-mediated correction of splicing rescues the disease phenotype in dysferlinopathy patient-derived cells. We aim to develop a new therapy for dysferlinopathy using an exon skipping strategy.

Last updated: 19 January, 2023