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      The fate of individual myoblasts after transplantation into muscles of DMD patients.

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      Publication date:
      Journal: Nature medicine
      Keywords: Cell Count, Cell Fusion, Cell Nucleus, pathology, Cell Transplantation, adverse effects, Dystrophin, genetics, metabolism, Gene Expression, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Muscles, transplantation, Muscular Dystrophies, therapy, T-Lymphocytes, immunology, Time Factors, Tissue Donors

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          Abstract

          Muscle biopsies from six patients with Duchenne muscular dystrophy (DMD) participating in a myoblast transplantation clinical trial were reexamined using a fluorescence in situ hybridization (FISH)-based method. Donor nuclei were detected in all biopsies analyzed, including nine where no donor myoblasts were previously thought to be present. In three patients, more than 10% of the original number of donor cells were calculated as present 6 months after implantation. Half of the detected donor nuclei were fused into host myofibers, and of these, nearly 50% produced dystrophin. These findings demonstrate that although donor myoblasts have persisted after injection, their microenvironment influences whether they fuse and express dystrophin. Our methodology could be used for developing new approaches to improve myoblast transfer efficacy and for the analysis of future gene- and/or cell-based therapies of numerous genetic disorders.

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          Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.

          O. Ibraghimov-Beskrovnaya, J Ervasti, C Leveille … (1992)
          The primary sequence of two components of the dystrophin-glycoprotein complex has been established by complementary, DNA cloning. The transmembrane 43K and extracellular 156K dystrophin-associated glycoproteins (DAGs) are encoded by a single messenger RNA and the extracellular 156K DAG binds laminin. Thus, the 156K DAG is a new laminin-binding glycoprotein which may provide a linkage between the sarcolemma and extracellular matrix. These results support the hypothesis that the dramatic reduction in the 156K DAG in Duchenne muscular dystrophy leads to a loss of a linkage between the sarcolemma and extracellular matrix and that this may render muscle fibres more susceptible to necrosis.
          Article 0 comments Cited 251 times – based on 0 reviews     Review now
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            Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy.

            L Specht, Nicholas E. Hoffman, John Loike … (1988)
            A deficiency of the protein dystrophin has recently been shown to be the probable cause of Duchenne's muscular dystrophy. We sought to determine the relation between the clinical phenotype and the status of dystrophin in muscle-biopsy specimens from 103 patients with various neuromuscular disorders. We found very low levels (less than 3 percent of normal levels) or no dystrophin in the severe Duchenne phenotype (35 of 38 patients), low concentrations of dystrophin in the intermediate (outlier) phenotype (4 of 7), and dystrophin of abnormal molecular weight in the mild Becker phenotype (12 of 18). Normal levels of dystrophin of normal molecular weight were found in nearly all the patients (38 of 40) with 20 other neuromuscular disorders we studied. These data show the clinical consequences of both quantitative alterations (in Duchenne's and intermediate dystrophy) in a single protein. The biochemical assay for dystrophin should prove helpful in delineating myopathies that overlap clinically with Duchenne's and Becker's dystrophies, and it shows promise as an accurate diagnostic tool.
            Article 0 comments Cited 115 times – based on 0 reviews     Review now
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              Myoblast transfer in the treatment of Duchenne's muscular dystrophy.

              Mark J. Mendell, Hamish W. King, David Amato … (1995)
              Myoblast transfer has been proposed as a technique to replace dystrophin, the skeletal-muscle protein that is deficient in Duchenne's muscular dystrophy. Donor myoblasts injected into muscles of affected patients can fuse with host muscle fibers, thus contributing their nuclei, which are potentially capable of replacing deficient gene products. Previous controlled trials involving a single transfer of myoblasts have been unsuccessful. We injected donor muscle cells once a month for six months to the biceps brachii muscles of one arm of each of 12 boys with Duchenne's muscular dystrophy. The opposite arms served as sham-injected controls. In each procedure 110 million cells donated by fathers or brothers were transferred. The patients were randomly assigned to receive either cyclosporine or placebo. Strength was measured by quantitative isometric muscle testing. Six months after the final myoblast transfer, the presence of dystrophin was assessed with the use of peptide antibodies specific to the deleted exons of the dystrophin gene. There was no significant difference in muscle strength between arms injected with myoblasts and sham-injected arms. In one patient, 10.3 percent of muscle fibers expressed donor-derived dystrophin after myoblast transfer. Three other patients also had a low level of donor dystrophin (< 1 percent); eight had none. Myoblasts transferred once a month for six months failed to improve strength in patients with Duchenne's muscular dystrophy. The value of exon-specific peptide antibodies in the interpretation of myoblast-transfer results was demonstrated in a patient with Duchenne's muscular dystrophy who had a high percentage of donor-derived dystrophin. Specific variables affecting the efficiency of myoblast transfer need to be identified in order to improve upon this technique.
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                Author and article information

                Journal
                PubMed ID:: 9288722
                DOI:: 10.1038/nm0997-970

                ScienceOpen disciplines: Chemistry
                Keywords: Cell Count,Cell Fusion,Cell Nucleus,pathology,Cell Transplantation,adverse effects,Dystrophin,genetics,metabolism,Gene Expression,Humans,Immunohistochemistry,In Situ Hybridization, Fluorescence,Male,Muscles,transplantation,Muscular Dystrophies,therapy,T-Lymphocytes,immunology,Time Factors,Tissue Donors
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                ScienceOpen disciplines: Chemistry
                Keywords: Cell Count, Cell Fusion, Cell Nucleus, pathology, Cell Transplantation, adverse effects, Dystrophin, genetics, metabolism, Gene Expression, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Muscles, transplantation, Muscular Dystrophies, therapy, T-Lymphocytes, immunology, Time Factors, Tissue Donors

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