An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells

Abstract

Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem (iPS) cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic iPS cells using a Sleeping Beauty transposon carrying the micro-utrophin (μUTRN) gene, differentiate these cells into skeletal muscle progenitors, and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance toward the future treatment of muscular dystrophies using genetically corrected autologous iPS cells.

Human satellite cells have regenerative capacity and are genetically manipulable

“…However, expansion of human satellite cells for therapeutic purposes has not been successful. Therefore, therapy-oriented research has favored the use of other cell populations with myogenic potential, such as CD133 + cells, pericytes, inducible stem cells, mesoangioblasts, or PW1 cells (10)(11)(12)(13)(14). These cells are abundant, more accessible, and transverse blood vessels.…”

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…Induced pluripotent stem cells are pluripotent cells with properties similar to embryonic stem cells obtained by reprogramming somatic cells such as fibroblasts [219,220]. In this sense, there were already experiences that demonstrated the possibility of producing myoblasts from induced pluripotent stem cells obtained from mice [221][222][223][224] and humans [225].…”

Gene Therapy in Monogenic Congenital Myopathies

“…Pluripotent stem cells may be able to replenish tissue loss through their indefinite self-replicating potential and capacity to be converted into nearly all cell types within the body. The advantages of combining stem cell therapy with gene therapy have been demonstrated in several animal studies, in which vectors were administered ex vivo and modified donor cells were later engrafted into native tissue [34][35][36] .…”