Cell Transplantation as an Experimental Treatment for Duchenne Muscular Dystrophy

Abstract

The feasibility, safety, and efficacy of myoblast transfer therapy (MIT) were assessed in an experimental lower body treatment (LBT) involving 32 Duchenne muscular dystrophy (DMD) boys aged 6-14 yr, half of whom were nonambulatory. Through 48 injections, five billion (55.6 x 10(6)/mL) normal myoblasts were transferred into 22 major muscles in both lower limbs, in 10 min with the subject under general anesthesia. Ten subjects received myoblasts cultured from satellite cells derived from 1-g fresh muscle biopsies of normal males aged 9-21 yr. Donor myoblasts for the remaining 22 boys were subcultured from reserves frozen 1 mo-1.5 yr ago. Only four donors were known to have identical histocompatibility with their recipients. All subjects took oral doses of the immunosuppressant cyclosporine (Cy), beginning at 2 days before MTT and lasting for 6 mo after MTT to facilitate donor cell survival. There was no evidence of an adverse reaction to MTT or Cy as determined by serial laboratory evaluations including electrolytes, creatinine, and urea. Objective functional tests using the KinCom Robotic Dynamometer measured the maximum isometric contractile forces of the ankle plantar flexors (AF), knee flexors (KF), and knee extensors (KE) before MTT and at 3, 6, and 9 mo after MTT. The AF, being distal muscles and less degenerative than the KE and the KF, showed no decrease in mean contractile force 3 mo after MTT, and progressive increases in force at 6 and 9 mo after MTT. At 9 mo after MTT, 60% of the 60 AF examined showed a mean increase of 50% in force; 28% showed no change; and only 12% showed a mean decrease in force of 29% when compared to the function of the same muscles before MTT. The KF, being proximal muscles and more degenerative, showed no change in function at 9 mo after MTT. The KE, being proximal and anti-gravitational, were most degenerative before MTT. They showed no statistically significant change in force at 3 mo after MTT but showed decreases at 6 and 9 mo after MTT. At 9 mo after MTT, 23% of the 60 KE examined showed a mean increase of 65% in force; 22% showed no change; and 55% showed a mean decrease of 24% in force. When results of all muscle groups (AF, KF, KE) were pooled, there was no change in force at 3, 6, or 9 mo after MTT vs. before MTT according to the Wilcoxon signed rank test.(ABSTRACT TRUNCATED AT 400 WORDS)

Advances in musculoskeletal tissue engineering

“…A stem cell is a cell able to self-renew continuously and to give rise to differentiation into various cell types through asymmetric division. 3 Stem cells are present in every developmental stage and are distinguishable on the basis of the developmental period in which they are present in embryonic, fetal and adult. Differences are related to their differentiation potential: embryonic stem (ES) cells can be derived from the inner blastocyst mass and can produce adult tissue from all three germ layers (ectoderm, mesoderm and endoderm); fetal cells retain a pluripotent differentiation potential, but more limited than the embryonic; in the postatal life (i.e., adult stem cells) however, there is a loss of plasticity, that passes through multipotency (capacity to form cells derived from the same germ layer) to unipotency (capacity to form only one specific type of adult cell).…”

Expression of Trisk�51, agrin and nicotinic-acetycholine receptor ?-subunit during muscle development in a novel three-dimensional muscle-neuronal co-culture system

“…This induces proliferation and fusion of myoblasts to form multinucleated elongated myotubes that self-assemble to form a more organized structure, namely a muscle fiber (Campion 1984;Schultz 1989;Hawke and Garry 2001). The implantation of engineered myoblasts has been utilized as a potential therapy for genetic muscle diseases such as Duchenne's muscular dystrophy or for the repair of damaged myocardial tissues (Gussoni et al 1992;Blau et al 1993;Law et al 1993;Fassati and Bresolin 2000;Gillis 2000;Marty et al 2000;Ye et al 2000b). These findings and the stimuli-responsive functional capabilities of skeletal muscle cells could have important clinical implications, among others, for myoblast transfer or for the transplantation of engineered muscle constructs.…”

Transplantation of myoblasts from a transgenic mouse overexpressing dystrophin produced only a relatively small increase of dystrophin-positive membrane

“…1,2,7,18,28,29,33,34 Clinical trials of myoblast transplantation have produced only limited results due in part to immunological problems. 8,10,14,19,25,26,40 Good transplantation results were indeed obtained following transplantation in immunodeficient and in adequately immunosuppressed mice. 16,17,22,30,35,43 The limited success of these trials was also due in part to the limited participation of the donor myoblasts to muscle regeneration due to diffusion barriers such as the basal lamina and the extracellular matrix.…”