Advanced therapeutic approaches in sarcoglycanopathies.

Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress.

Modeling Sarcoglycanopathy in .

Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and β-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood.

CFTR corrector C17 is effective in muscular dystrophy, in vivo proof of concept in LGMDR3.

Limb-girdle muscular dystrophy R3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional α-SG.