TRANSPLANTATION OF DERMAL FIBROBLASTS EXPRESSING MYOD1 IN MOUSE MUSCLES

Transplantation of normal myoblasts into dystrophic muscles is a poten tial treatment for Duchenne muscular dystrophy (DMD). However, the suc cess of such grafts is limited by the immune system responses. To avoi d rejection problems, autologous transplantation of the patient's corr ected myoblasts has been proposed. Regretfully, the low proliferative capacity of DMD myoblasts in culture (due to their premature senescenc e) limits such procedure. On the other hand, modification of dermal fi broblasts leading to the myogenic pathway using a master regulatory ge ne for myogenesis is an interesting alternative approach. In this stud y, the retrovirally encoded MyoD1 cDNA was introduced in dermal fibrob lasts of TnI LacZ mice to provoke their conversion into myoblast-like cells. In vitro and in vivo assays were done and the results were comp ared to those obtained with uninfected fibroblasts and myoblasts. Some MyoD1-expressing fibroblasts were able to fuse and to express beta-ga lactosidase (under the transcriptional control of the Troponin I promo ter), dystrophin and desmin in vitro. Thirty days following implantati on of these modified fibroblasts in muscles of mdx mice, an average of 7 beta-Gal+/Dysmuscle fibers were observed. No beta-Gal+ fibers were observed after the transplantation of uninfected fibroblasts. Our resu lts indicate that the successful implantation of myoblasts obtained fr om genetically modified fibroblasts is indeed feasible. However, the i n vitro conversion rate and the in vivo fusion of genetically modified fibroblasts must be largely increased to consider this approach as a potential therapy for DMD and other myopathies. (C) 1998 Academic Pres s.