Peripheral tolerance, regulatory T cells and myoblast transfer therapy

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[Truncated abstract] Of the 700 neuromuscular diseases currently described in man Duchenne Muscular Dystrophy (DMD) is both the most common and most severe of those diseases affecting primary muscle function. Mutations in the dystrophin gene result in the loss of dystrophin or production of a non-functional dystrophin protein, an essential element in the membrane stabilising machinery of muscle fibres. DMD is an X-linked recessive disease that affects about 1 in 3500 live male births. Males suffer almost exclusively from the crippling pathology of this disease due to their lack of a second X chromosome with a competent dystrophin gene. The dystrophin gene is one of the largest known human genes making it particularly susceptible to random mutations. In fact approximately one third of cases arise with no prior family history of the disease. There is no cure for DMD and despite decades of research only palliative treatment is available to sufferers. Myoblast Transfer Therapy (MTT) is aimed at utilising the muscles natural repair mechanism via the direct injection of donor myoblasts (muscle precursor cells), which express functional dystrophin, into the damaged, dystrophic, tissue in order to provide a cell-based gene rescue. The objective of this procedure is for the donor myoblasts, upon injection into dystrophic muscle, to migrate throughout the tissue and fuse with host myoblasts to form what is referred to as mosaic muscle fibres. Whilst numerous animal model studies and some human clinical trials have indicated the MTT approach to be feasible in principle, myoblast death and immune rejection appears to limit the practicality of this potential therapy. The rapid disappearance of donor myoblasts from transplanted muscles after MTT is one of the most controversial and significant obstacles facing research in this area. A commonly used method to detect cell survival is quantitation of the Y chromosome following transplantation of male donor cells into female
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2009


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