Correction of the dystrophic phenotype by in vivo targeting of muscle progenitor cells.
Successful gene therapy for most inherited diseases will require stable expression of the therapeutic gene. This can be addressed with integrating or self-replicating viruses by targeting postmitotic cells that have a long lifetime or stem cells that can replenish defective tissue with corrected cells. In this study, we explore the possibility of targeting a muscle stem cell population in situ through in vivo administration of vector. To develop this concept, we selected a mouse model of muscular dystrophy (mdx mice) that undergoes rapid turnover of muscle fibers. In vivo targeting of muscle progenitor cells, notably satellite cells, with a pseudotyped lentiviral vector encoding the minidystrophin restores dystrophin expression and provides functional correction in skeletal muscle of mdx mice. This study shows that progenitor cells can be genetically engineered in vivo and subsequently proliferate into terminally differentiated tissue carrying the genetic graft in a way that stably corrects function.
Gene Therapy Program, Division of Medical Genetics, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
Gary P
GP
Kobinger
Jean-Pierre
JP
Louboutin
Elisabeth R
ER
Barton
H Lee
HL
Sweeney
James M
JM
Wilson
D000818:Animals; D002454:Cell Differentiation; D004396:Coloring Agents / Q000494:pharmacology; D016189:Dystrophin / Q000235:genetics; D005070:Evans Blue / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D009136:Muscular Dystrophies / Q000235:genetics*; D009336:Necrosis; D010641:Phenotype; D013234:Stem Cells; D001616:beta-Galactosidase / Q000378:metabolism
D004396:Coloring Agents; D016189:Dystrophin; D005070:Evans Blue; D001616:beta-Galactosidase