Myoblast Therapies Constitute a Safe and Efficacious Platform Technology of Regenerative Medicine for the Human Health Industry
Peter K. LawWenbin LiQibin SongShi Jun SongJun RenManye YaoQiaoyun LiQizhong ShiKeqiang WangJing WangLei YeJianhua MaKhawaja Husnain HaiderLiping SuPing LüWeyland ChengMing Zhang AoDanlin M. Law
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Intramuscular implantation of cultured allogeneic myoblasts derived from pathogen-free muscle biopsies of genetically normal human volunteers demonstrated safety and efficacy in clinical studies of Duchenne muscular dystrophy (DMD), heart failure, ischemic cardiomyopathy, Type-II diabetes, cancer, and aging disfigurement. Through natural cell fusion, donor myoblasts inserted their normal nuclei that supplied the complete human genome to replenish the aberrant gene(s). The replacement gene(s) produced single or multiple gene transcripts, factors, and protein(s) in multiple pathways to effect complementary genetic repair. Donor myoblasts also fused among themselves to form normal myofibers. Applications included diagnostic screening, disease prevention, disease treatment, drug discovery, and selection of superior cell clones for therapies. Only 3-week cyclosporine immunosuppression was necessary to support engraftment, development, and functioning. Improvement in the host included production of repairing structural and regulatory proteins, increases in muscle cell number and function, increases in locomotive capacity, breathing capacity and life span in DMD boys, increases in blood ejection and vascularization in heart failure and ischemic patients, and transfer of biochemicals and ions across the muscle cell membrane in diabetic patients. Intra-tumor implantation of allogeneic human myoblasts induced cancer apoptosis, inhibiting metastasis and tumor growth with cancer patients. FDA currently listed 23 myoblast implantation projects, and EMA listed 6, mostly in Phase II with some in Phase III clinical trials. This unique platform technology, patented for its compositions, methods, and related medical devices of cell/gene therapies, promised to be of great social and economic values in world health and human services.Backgrounds. Implantation of normal myoblasts may eventually be a treatment for inherited myopathies such as Duchenne muscular dystrophy. Methods. We report a comparative study of the effectiveness on myoblast implantation: (1) into the muscles of young (2 months) mdx mice nonirradiated and noninjected with notexin (group 1), (2) into muscles of old mdx mice (15 months) nonirradiated and noninjected with notexin (group 2), and (3) into muscles of 5 months mdx mice irradiated 3 months before the transplantation (group 3). Roughly 3 million cells were injected with bFGF in the Tibialis anterior. Results. Although mice of groups 2 and 3 had significantly more (P<0.05) fibrotic tissue in their muscles than those of group 1, the transplantation success was not significantly different among the three groups. Conclusion. Therefore these results demonstrated that myoblast transplantation can be successful even when there is abundant fibrosis.
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Myoblast transplantation has long been studied as a potential therapy for Duchenne muscular dystrophy as the incorporation of donor myoblasts into host muscle allows the production of functional dystrophin protein. However, the clinical feasibility of this approach is limited by the poor survival of the donor cells in the weeks after transplantation. It has recently been determined that the intramuscular transplantation of large numbers of cells can lead to the formation of ischemic necrosis in the center of these cell masses. For this reason, the relationship between donor cell survival and the number of cells transplanted was investigated.Myoblasts were prepared from the hind limb muscles of male C57BL/10Sn mice and transplanted into the tibialis anterior muscles of female mdx mice at one of the following amounts: 10, 10, 10, or 10 cells. The survival of the transplanted cells was analyzed using a Y chromosome-specific qPCR.It was found that donor cell survival was improved 1 week after transplantation when fewer myoblasts were transplanted, including the observation of donor cell proliferation after the transplantation of 10 myoblasts. However, concentration effects and long-term survival complicate the interpretation of these results.These results indicate that early donor myoblast survival was dependent on the number of cells transplanted and the volume of liquid used to deliver them into the muscle. We believe that this finding has implications for the design and interpretation of future experimentation relating to intramuscular cell therapies.
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Abstract A possible treatment for Duchenne muscular dystrophy is the injection of normal myoblasts into dystrophic muscles to induce the formation of new, healthy, and dystrophin‐positive muscle fibers. To develop this therapy, it is important to identify the muscle fibers formed by the injected myoblasts in the host muscles. In this study, we used myoblasts from transgenic mice which have a gene expressing β‐galactosidase under the control of the promoter of quail fast skeletal muscle troponin I. This transgene is expressed in myotubes and muscle fibers, but not in myoblasts. Twenty‐eight days after myoblast transplantation in nude and in mdx mice, muscle fibers containing of β‐galactosidase were identified by x‐gal staining. In mdx mice, most of the β‐galactosidase‐positive muscle fibers resulting from the myoblast transplantation were also dystrophin positive. This technique could make it possible to follow the success of myoblast transplantation even in mice that are not depleted of dystrophin. © 1994 John Wiley & Sons, Inc.
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Duchenne muscular dystrophy (DMD) is a progressive disease that leads to damage of muscle and myocardium due to genetic abnormalities in the dystrophin gene. In utero cell transplantation that might facilitate allogenic transplantation is worth considering to treat this disease.We performed allogeneic in utero transplantation of GFP-positive myoblasts and adipose-derived mesenchymal stem cells into murine DMD model animals. The transplantation route in this study was fetal intraperitoneal transplantation and transplacental transplantation. Transplanted animals were examined at 4-weeks old by immunofluorescence staining and RT-qPCR.No GFP-positive cells were found by immunofluorescence staining of skeletal muscle and no GFP mRNA was detected by RT-qPCR in any animal, transplantation method and cell type. Compared with previous reports, myoblast transplantation exhibited an equivalent mortality rate, but adipose-derived stem cell (ASC) transplantation produced a higher mortality rate.In utero transplantation of myoblasts or ASCs to murine models of DMD does not lead to engraftment and, in ASC transplantation primarily, frequently results in fetal death.
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Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.
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To study the fusion of transplanted myoblast with host muscle cells and the expression of dystrophin in the muscle of mdx mice model for Duchenne muscular dystrophy (DMD) after local co-transplantation of myoblasts and schwann cells.Myoblasts and schwann cells were prepared with gastrocnemius muscle taken from newborn C57BL/10 mice. Twenty four mdx mice were divided into two groups, one group received the injection of myoblasts into gastrocnemius muscle of left behind limb of mdx mice, another group received the cotransplantation of schwann cells and myoblasts in a ratio of 1:10. The cells were transplanted to host mice once a week for four times. The mdx mice were sacrificed one month later, the expression of dystrophin in gastrocnemius muscle was measured, and the pathological and immunohistochemistry exams were performed.The IOD of dystrophin of left gastrocnemius in co-transplantation group and myoblast transplantation group were 6342429.4167 +/- 925414.20068 and 5295615.7500 +/- 1243283.86373,respectively. The difference showed statistical significance, which indicated that the expression of dystrophin in co-transplantation group was higher than that of myoblast transplantation group.local co-transplantation of myoblast and schwann cell can improve the myoblast's fusion after transplantation.
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