Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy

• Published in: Scientific reports Vol. 6; no. 1; p. 19750
• Main Authors: Meng, Jinhong, Counsell, John R, Reza, Mojgan, Laval, Steven H, Danos, Olivier, Thrasher, Adrian, Lochmüller, Hanns, Muntoni, Francesco, Morgan, Jennifer E
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.01.2016
• Subjects: Animals; Autografts; Cell Differentiation; Cell- and Tissue-Based Therapy; Disease Models, Animal; Duchenne's muscular dystrophy; Dystrophin; Dystrophin - genetics; Dystrophin - metabolism; Gene Expression; Genetic Therapy; Genetic Vectors; Humans; Immunodeficiency; Lentivirus - genetics; Mice; Mice, Inbred mdx; Mice, Nude; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - metabolism; Muscular dystrophy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - therapy; Musculoskeletal system; Myoblasts - cytology; Myoblasts - metabolism; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Pericytes - cytology; Pericytes - metabolism; Pericytes - transplantation; Protein Binding; Recombinant Fusion Proteins; Rodents; Skeletal muscle; Stem cell transplantation; Stem cells; Transduction, Genetic
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19750

Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation.