Hematopoietic Cell Transplantation Provides an Immune-tolerant Platform for Myoblast Transplantation in Dystrophic Dogs

Program in Transplantation Biology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Molecular Therapy (Impact Factor: 6.23). 08/2008; 16(7):1340-6. DOI: 10.1038/mt.2008.102
Source: PubMed

ABSTRACT Duchenne Muscular Dystrophy (DMD) is the most common and severe form of muscular dystrophy in humans. The goal of myogenic stem cell transplant therapy for DMD is to increase dystrophin expression in existing muscle fibers and to provide a source of stem cells for future muscle generation. Although syngeneic myogenic stem cell transplants have been successful in mice, allogeneic transplants of myogenic stem cells were ineffective in several human trials. To determine whether allogeneic muscle progenitor cells can be successfully transplanted in an immune-tolerant recipient, we induced immune tolerance in two DMD-affected (cxmd) dogs through hematopoietic cell transplantation (HCT). Injection of freshly isolated muscle-derived cells from the HCT donor into either fully or partially chimeric xmd recipients restored dystrophin expression up to 6.48% of wild-type levels, reduced the number of centrally located nuclei, and improved muscle structure. Dystrophin expression was maintained for at least 24 weeks. Taken together, these data indicate that immune tolerance to donor myoblasts provides an important platform from which to further improve myoblast transplantation, with the goal of restoring dystrophin expression to patients with DMD.

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    • "They used a lentivirus vector to introduce a dog microdystrophin cDNA into dystrophic dog muscle precursor cells and then injected these transfected cells into normal dogs (Pichavant et al. 2010). Others have shown that the level of myoblast implantation can potentially be increased in GRMD dogs by first inducing tolerance through hematopoietic cell transplantation (Parker et al. 2008). In a separate earlier study, cardiomyocytes were stably engrafted in the hearts of GRMD dogs (Koh et al. 1995). "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene- and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. Various phenotypic tests have been developed to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. A number of these studies have provided largely general proof-of-concept for the treatment under study. Others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. Though confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified.
    Mammalian Genome 01/2012; 23(1-2):85-108. DOI:10.1007/s00335-011-9382-y · 3.07 Impact Factor
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    • "In a study of seven CXMD dogs that underwent allo-HSCT from non-affected littermates, there was no increase in the number of dystrophin-positive fibers or in the amount of wild-type dystrophin RNA post-transplantation compared with pre-transplantation levels. However, another canine study demonstrated that allo-HSCT provides an immune-tolerant platform for myoblast transplantation from freshly isolated muscle-derived cells from the same HSCT donor [15]. "
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    ABSTRACT: Diamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental. We report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemia and Duchenne muscular dystrophy who underwent successful allogeneic hematopoietic stem cell transplantation. He is transfusion-independent, and his Duchenne muscular dystrophy has shown no clinical deterioration over the past 45 months. His creatine phosphokinase levels have significantly decreased to 300 U/L from 14,000 U/L pre-transplant. The patient is 100% donor chimera in the hematopoietic system, and his muscle tissue has shown 8% to 10.4% cells of donor origin. Our patient's Diamond-Blackfan anemia was cured by allogeneic hematopoietic stem cell transplantation. The interesting clinical observation of a possible benefit in Duchenne muscular dystrophy cannot be ruled out. However, further clinical follow-up with serial muscle biopsies and molecular studies are needed to establish this finding.
    Journal of Medical Case Reports 06/2011; 5:216. DOI:10.1186/1752-1947-5-216
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    • "This strategy has successfully induced tolerance to donor-derived solid organ transplantation (e.g., kidney, liver and pancreatic islet cells) in mice and dogs without the need for long-term conventional immunosuppression (Kuhr et al. 2007b). A recent study using cxmd dogs (Parker et al. 2008) demonstrated that DLA-identical HCT provided an immune-tolerant platform for subsequent transplantation and stable engraftment of HSC donor-derived myoblasts in the absence of pharmacological immunosuppression. Two chimeric dystrophic dogs received intramuscular injections of freshly isolated myoblasts. "
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    ABSTRACT: The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases characterized by progressive muscle wasting, which can lead to premature death in severe forms such as Duchenne muscular dystrophy (DMD). In many cases they are caused by the absence of proteins that are critical components of the dystrophin-glycoprotein complex, which links the cytoskeleton and the basal lamina. There is no effective treatment for these disorders at present, but several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. We review these strategies, which include the use of stem cells of different tissue origins, gene replacement therapies mediated by various viral vectors, and transcript repair treatments using exon skipping strategies. We comment on their advantages and on limitations that must be overcome before successful application to human patients. Our focus is on studies in a clinically relevant large canine model of DMD. Recent advances in the field suggest that effective therapies for muscular dystrophies are on the horizon. Because of the complex nature of these diseases, it may be necessary to combine multiple approaches to achieve a successful treatment.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/2009; 50(2):187-98. DOI:10.1093/ilar.50.2.187 · 2.39 Impact Factor
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