Partridge, TA, Morgan, JE, Coulton, GR, Hoffman, EP and Kunkel, LM. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337: 176-179
ABSTRACT An important corollary to the recent advances in our understanding of the primary cause of Duchenne muscular dystrophy, is the validation of genuine genetic homologues as animal models of the disease in which potential therapies can be tested. The persistent skeletal muscle necrosis that characterizes human Duchenne muscular dystrophy is also seen in the mdx mouse and is, in both, a consequence of a deficiency of dystrophin, probably within the muscle fibres themselves. As injected muscle precursor cells of one genotype can fuse with host muscle fibres of a different genotype and express the donor genes, we decided to test grafts of normal muscle precursor cells to see if they could induce synthesis of dystrophin in innately dystrophin-deficient mdx muscle fibres. We show that injected normal muscle precursor cells can fuse with pre-existing or regenerating mdx muscle fibres to render many of these fibres dystrophin-positive and so to partially or wholly rescue them from their biochemical defect.
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- "Transplantation of allogeneic myoblasts into injured muscle has been extensively investigated, especially as therapy for DMD. The initial preclinical demonstration that myoblast transplantation could restore dystrophin expression in animal models occurred as early as 1989 (Partridge et al., 1989). A series of clinical trials resulting in unfavorable outcomes were soon to follow (Gussoni et al., 1992; Huard et al., 1994, 1991; Karpati et al., 1993; Tremblay et al., 1993a,b; Miller et al., 1997). "
ABSTRACT: The well-recognized ability of skeletal muscle for functional and structural regeneration following injury is severely compromised in degenerative diseases and in volumetric muscle loss. Tissue engineering and regenerative medicine strategies to support muscle reconstruction have typically been cell-centric with approaches that involve the exogenous delivery of cells with myogenic potential. These strategies have been limited by poor cell viability and engraftment into host tissue. Alternative approaches have involved the use of biomaterial scaffolds as substrates or delivery vehicles for exogenous myogenic progenitor cells. Acellular biomaterial scaffolds composed of mammalian extracellular matrix (ECM) have also been used as an inductive niche to promote the recruitment and differentiation of endogenous myogenic progenitor cells. An acellular approach, which activates or utilizes endogenous cell sources, obviates the need for exogenous cell administration and provides an advantage for clinical translation. The present review examines the state of tissue engineering and regenerative medicine therapies directed at augmenting the skeletal muscle response to injury and presents the pros and cons of each with respect to clinical translation. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 01/2014; 297(1). DOI:10.1002/ar.22794 · 1.53 Impact Factor
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- "In the present study, we tested the specificity with which individual antibodies that recognize proteins of human, not mouse, origin track the presence of transplanted human cells. Three immune-deficient mouse models were analyzed: NOD/Rag1 null mdx5 cv and mdx/nude, which carry a mutation in the dystrophin gene (Partridge et al., 1989; Boldrin et al., 2012; Lapan et al., 2012); and the NSG immune-deficient model (Shultz et al., 2005, 2007), where the muscle was preinjured with cardiotoxin or by cryoinjury or irradiation followed by cryoinjury. It was found that detection of engrafted human cells, using antihuman-specific spectrin, results in visualization of falsepositive myofibers in all three murine models. "
ABSTRACT: Stem cell transplantation is being tested as a potential therapy for a number of diseases. Stem cells isolated directly from tissue specimens or generated via reprogramming of differentiated cells require rigorous testing for both safety and efficacy in pre-clinical models. The availability of mice with immune-deficient background that carry additional mutations in specific genes facilitates testing the efficacy of cell transplantation in disease models. The muscular dystrophies are a heterogeneous group of disorders, of which Duchenne muscular dystrophy is the most severe and common type. Cell based therapy for muscular dystrophy has been under investigation for a few decades, with a wide selection of cell types being studied, including tissue-specific stem cells and reprogrammed stem cells. Several immune deficient mouse models of muscular dystrophy have been generated, where human cells obtained from various sources are injected to assess their pre-clinical potential. Following transplantation, the presence of engrafted human cells is detected via immunofluorescence staining using antibodies that recognize human, but not mouse, proteins. Here we show that one antibody specific to human spectrin, which is commonly used to evaluate the efficacy of transplanted human cells in mouse muscle, detects myofibers in muscles of NODRag1null mdx5cv, NSG mice or mdx nude mice, irrespective of whether they were injected with human cells. These 'reactive' clusters are regenerating myofibers, which are normally present in dystrophic tissue and the spectrin antibody is likely recognizing utrophin, which contains spectrin-like repeats. Therefore, caution should be used in interpreting data based on detection of single human-specific proteins and evaluation of human stem cell engraftment should be performed using multiple human-specific labeling strategies.Human gene therapy 10/2013; DOI:10.1089/hum.2013.126 · 3.62 Impact Factor
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- "Exogenous nuclei can then express therapeutic genes in myofibers that previously suffered from a genetic deficiency. The first report of gene complementation restoring a genetically missing protein in a myopathic animal was of Partridge et al. in 1989 . They transplanted normal mouse myoblasts in skeletal muscles of mdx mice, a mouse strain that develops a myopathy caused by the lack of dystrophin as DMD in humans. "
ABSTRACT: Myopathies produce deficits in skeletal muscle function and, in some cases, progressive and irreversible loss of skeletal muscles. The transplantation of myogenic cells, that is, cells able to differentiate into myofibers, is an experimental strategy for the potential treatment of some of these diseases. The objectives pursued by the transplantation of these cells are essentially three: (a) the fusion with the patient’s myofibers to obtain the expression of therapeutic proteins into them, (b) the neoformation of new functional myofibers in skeletal muscles that were too degenerated by the progressive degeneration, and (c) the formation of a new pool of healthy donor-derived satellite cells. Although the repertoire of myogenic cells appears to have expanded in recent years, myoblasts are the only cells that have been demonstrated to engraft in humans. The present work aims to make a comprehensive review of the subject, from its beginnings to recent advances, including the preclinical experience in different animal models and recent clinical findings.10/2013; 2013. DOI:10.5402/2013/582689