Myoblast transfer and gene therapy in muscular dystrophies

Abstract

Myoblast transfer therapy and gene therapy have both been proposed as potential treatments for inherited myopathies, such as Duchenne muscular dystrophy (DMD). The success of myoblast implantation in mouse models, where problems such as immune rejection are easily overcome, have led to similar experiments being attempted on Duchenne patients with limited, if any, success. Gene therapy, either by viral vectors or direct injection of the plasmid, has also had some success in animal models. Although both techniques, either separately or in combination, show some promise for the treatment of DMD, there are still many issues to be investigated in animal models, including the following: What is the best source of muscle precursor cells (mpc), and how may sufficient cells be obtained? What is the best vehicle for gene therapy? How far from the injection site can an implanted cell or gene have an effect? How can immune rejection of the injected cells or introduced protein be overcome? Does the introduced dystrophin lead to improved muscle function? Can cardiac muscle can be successfully treated by gene therapy? Can skeletal muscle which has undergone a great deal of damage be improved by either cell or gene therapy?

Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

“…The very idea that myoblast transfer is a conceptually viable approach to treat myopathies originated over 20 years ago from a fundamental understanding about how multinucleated skeletal muscle is formed. 16 Since then, a combination of studies in cell lines and mice has delineated the specific roles of a family of muscle regulatory transcription factors (MRFs) composed of MyoD, Myogenin, Myf-5 and MRF4. Much is also known about the signaling pathways regulating the MRFs.…”

High efficiency transduction of human VEGF165 into human skeletal myoblasts: in vitro studies

“…The feasibility of ex-vivo cell mediated gene transfer is being widely investigated (Pagel et al, 1995;Floyd et al, 1998). More recently, genetically engineered myoblast mediated FGF2 delivery for revasularization in a model of acute skin flap ischemia has been documented (Rinch et al, 2001).…”

Immune rejection of human dystrophin following intramuscular injections of naked DNA in mdx mice

“…Similar features were reported in the mdx mouse model after allo-or xenogenic cell graft 10,22,23 or after viral vector administration. 24,25 Myoblast graft presents an unfavorable context from the immunological point of view, since in addition to the transgene itself, the cell vector as well as multiple culture medium protein factors, which bear many antigenic determinants, may trigger immune rejection. Despite this immune barrier, improvement of muscle strength was reported admittedly in few of the myoblast graft clinical trials.…”