SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy

• Published in: Molecular therapy Vol. 25; no. 6; pp. 1395 - 1407
• Main Authors: Sarathy, Apurva, Wuebbles, Ryan D., Fontelonga, Tatiana M., Tarchione, Ashley R., Mathews Griner, Lesley A., Heredia, Dante J., Nunes, Andreia M., Duan, Suzann, Brewer, Paul D., Van Ry, Tyler, Hennig, Grant W., Gould, Thomas W., Dulcey, Andrés E., Wang, Amy, Xu, Xin, Chen, Catherine Z., Hu, Xin, Zheng, Wei, Southall, Noel, Ferrer, Marc, Marugan, Juan, Burkin, Dean J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.06.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Actin; Alanine; Animals; Cardiac muscle; Cell Differentiation - drug effects; Cell Line; Cell lines; Contraction; Cytoskeleton; Disease Models, Animal; Disease Progression; Drug dosages; Duchenne muscular dystrophy; Duchenne's muscular dystrophy; Dystrophin; Enhancers; Experiments; Extracellular matrix; Female; Fibrosis; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Inflammation; Integrins - agonists; Integrins - metabolism; Kinases; Laminin; Mice; Mice, Inbred mdx; Models, Biological; Muscle contraction; Muscle Development - drug effects; Muscle Strength; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscular dystrophy; Muscular Dystrophy, Duchenne - drug therapy; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; Musculoskeletal system; Mutation; Myoblasts, Skeletal - cytology; Myoblasts, Skeletal - drug effects; Myoblasts, Skeletal - metabolism; NF-kappa B - metabolism; NF-κB protein; Oral administration; Original; Patients; Proline; Protein-Serine-Threonine Kinases - metabolism; Proteins; Regeneration - drug effects; Rodents; Sarcolemma; Signal Transduction - drug effects; Skeletal muscle; small molecule therapy; Software; Transcription; α7β1; Nevada; small molecule therapy; Duchenne muscular dystrophy; α7β1
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.03.022

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by mutations in the dystrophin gene, resulting in a complete loss of the dystrophin protein. Dystrophin is a critical component of the dystrophin glycoprotein complex (DGC), which links laminin in the extracellular matrix to the actin cytoskeleton within myofibers and provides resistance to shear stresses during muscle activity. Loss of dystrophin in DMD patients results in a fragile sarcolemma prone to contraction-induced muscle damage. The α7β1 integrin is a laminin receptor protein complex in skeletal and cardiac muscle and a major modifier of disease progression in DMD. In a muscle cell-based screen for α7 integrin transcriptional enhancers, we identified a small molecule, SU9516, that promoted increased α7β1 integrin expression. Here we show that SU9516 leads to increased α7B integrin in murine C2C12 and human DMD patient myogenic cell lines. Oral administration of SU9516 in the mdx mouse model of DMD increased α7β1 integrin in skeletal muscle, ameliorated pathology, and improved muscle function. We show that these improvements are mediated through SU9516 inhibitory actions on the p65-NF-κB pro-inflammatory and Ste20-related proline alanine rich kinase (SPAK)/OSR1 signaling pathways. This study identifies a first in-class α7 integrin-enhancing small-molecule compound with potential for the treatment of DMD. Duchenne muscular dystrophy is a fatal muscle disease with no cure. Using a muscle cell-based assay, Burkin and colleagues identified SU9516 as an α7 integrin-enhancing small molecule with novel mechanisms of action. They show that a mouse model of DMD treated with SU9516 exhibits reduced pathology and improved muscle strength.