? 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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR054955-02
Application #
7436331
Study Section
Special Emphasis Panel (ZAR1-EHB-H (J1))
Program Officer
Nuckolls, Glen H
Project Start
2007-06-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$81,340
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Janebodin, Kajohnkiart; Horst, Orapin V; Ieronimakis, Nicholas et al. (2011) Isolation and characterization of neural crest-derived stem cells from dental pulp of neonatal mice. PLoS One 6:e27526
Ieronimakis, Nicholas; Balasundaram, Gayathri; Rainey, Sabrina et al. (2010) Absence of CD34 on murine skeletal muscle satellite cells marks a reversible state of activation during acute injury. PLoS One 5:e10920
Ieronimakis, Nicholas; Balasundaram, Gayathri; Reyes, Morayma (2008) Direct isolation, culture and transplant of mouse skeletal muscle derived endothelial cells with angiogenic potential. PLoS One 3:e0001753