Myoblast implantation in Duchenne muscular dystrophy: The San Francisco study

Miller, Robert G.; Sharma, Khema R.; Pavlath, Grace K.; Gussoni, Emanuela; Mynhier, Mark A.; Yu, Pearl L.; Lanctot, Amy; Greco, Carolina; Steinman, Lawrence; Blau, Helen M.

doi:10.1002/(sici)1097-4598(199704)20:4<469::aid-mus10>3.0.co;2-u

Cited by 172 publications

(57 citation statements)

References 42 publications

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“…Thus far, the most notable stem cell approach for DMD involved intramuscular transplantation of satellite cell-derived myoblasts from normal individuals into dystrophic muscles. Based on proof of principle studies in the mdx mouse [159], several human trials were instituted, with largely disappointing results [160, 161]. Most transplanted cells probably died due to the combined effects of poor blood supply and immune rejection; those that survived demonstrated limited migration [162–164].…”

Section: The Golden Retriever Modelmentioning

confidence: 99%

The golden retriever model of Duchenne muscular dystrophy

2017

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Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about the poor rate of translation of animal model preclinical studies to humans with analogous diseases. Accordingly, in performing GRMD trials, special attention must be paid to experimental design to align with the approach used in DMD clinical trials. This review provides context for the GRMD model, beginning with its original description and extending to its use in preclinical trials.

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Section: The Golden Retriever Modelmentioning

confidence: 99%

The golden retriever model of Duchenne muscular dystrophy

2017

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“…One serial study suggested that MRI is more sensitive than functional tests in predicting disease progression (Liu et al 1993). MRI has also been used to monitor DMD disease progression in treatment trials (Karpati et al 1993; Miller et al 1997). …”

Section: Biomarkers For Assessment Of the Natural History And Responsmentioning

confidence: 99%

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

et al. 2012

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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. We and others have developed various phenotypic tests 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. While some of these studies have largely provided 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. While 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.

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“…Limb muscles have also been the main focus in studies on the potential of SCs as donor cells to alleviate muscle wasting, especially in dystrophinopathy. Despite their myogenic aptitude, enthusiasm for using limb SC-derived myoblasts has been weakened by their limited expandability and engraftment outcomes (Konieczny et al., 2013; Miller et al, 1997; Tremblay et al, 1993; Wilschut et al, 2012). This drawback may be related to heterogeneity in limb SC “stemness” with only a minority of cells appearing capable of both progeny production and self-renewal (Day et al, 2010; Kuang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

Stuelsatz

Shearer

et al. 2015

Developmental Biology

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Extraocular muscles (EOMs) are highly specialized skeletal muscles that originate from the head mesoderm and control eye movements. EOMs are uniquely spared in Duchenne muscular dystrophy and animal models of dystrophin deficiency. Specific traits of myogenic progenitors may be determinants of this preferential sparing, but very little is known about the myogenic cells in this muscle group. While satellite cells (SCs) have long been recognized as the main source of myogenic cells in adult muscle, most of the knowledge about these cells comes from the prototypic limb muscles. In this study, we show that EOMs, regardless of their distinctive Pax3-negative lineage origin, harbor SCs that share a common signature (Pax7+, Ki67−, Nestin-GFP+, Myf5nLacZ+, MyoD-positive lineage origin) with their limb and diaphragm somite-derived counterparts, but are remarkably endowed with a high proliferative potential as revealed in cell culture assays. Specifically, we demonstrate that in adult as well as in aging mice, EOM SCs possess a superior expansion capacity, contributing significantly more proliferating, differentiating and renewal progeny than their limb and diaphragm counterparts. These robust growth and renewal properties are maintained by EOM SCs isolated from dystrophin-null (mdx) mice, while SCs from muscles affected by dystrophin deficiency (i.e., limb and diaphragm) expand poorly in vitro. EOM SCs also retain higher performance in cell transplantation assays in which donor cells were engrafted into host mdx limb muscle. Collectively, our study provides a comprehensive picture of EOM myogenic progenitors, showing that while these cells share common hallmarks with the prototypic SCs in somite-derived muscles, they distinctively feature robust growth and renewal capacities that warrant the title of high performance myo-engines and promote consideration of their properties for developing new approaches in cell-based therapy to combat skeletal muscle wasting.

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Myoblast implantation in Duchenne muscular dystrophy: The San Francisco study

Cited by 172 publications

References 42 publications

The golden retriever model of Duchenne muscular dystrophy

The golden retriever model of Duchenne muscular dystrophy

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency

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