Adult muscle stem cells as cell therapy in utrophin-dystrophin deficient mice

[unreadable] DESCRIPTION (provided by applicant): [unreadable] DMD is a candidate disease for cell therapy for several reasons. There is no cure for this lethal and common genetic disorder of children, and current interventions act only to slow disease progression and maintain ventilation. DMD is recessively inherited, suggesting that dystrophin or utrophin replacement would be therapeutic. Numerous animal models are available, including several mouse models (mdx and mdx-utrn-/- mice) and cxmd dogs. Trials for gene therapy or cell therapy with myoblasts have not been very successful. An approach that warrants stable integration, constitutive expression and systemic delivery not just in skeletal muscle but also in cardiac muscle and smooth muscle is needed. MAPC can be isolated from adult bone marrow and skeletal muscle, massively expanded, stably transduced, can be differentiated in vitro into many tissue cell types including skeletal myoblasts and showed broad biodistribution when transplanted intraarterially. In this application, Aim 1, we propose to initially characterize, in detail, MAPC isolated from a severe dystrophic model that more closely mimics human DMD, mdx/utrn mouse. Understanding the properties of stem cells derived from dystrophic muscle is important to explore and develop the potential of these cells for cell therapy of muscular dystrophy. In Aim 2, we intend to study the outcome of syngeneic transplants of wt MAPC into mdx/utrn mice. In Aim 3, we will model an autologous transplant using mdx-utrn-/- MAPC transduced with a lentiviral vector carrying utrophin. The experiments proposed in this grant will lay the grounds to develop strategies for autologous cell therapy in a bigger animal model, the canine model for muscular dystrophy (cxmd), and if successful, human clinical trails. [unreadable] [unreadable] [unreadable]