Therapeutics in Duchenne muscular dystrophy

Strober, Jonathan B.

doi:10.1016/j.nurx.2006.01.005

Cited by 41 publications

(26 citation statements)

References 99 publications

(84 reference statements)

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“…By week 24 when consistent increases in dystrophin positive fibers were observed, one of the twins lost ambulation and the other was teetering on loss. In retrospect their baseline profile predicted imminent loss of ambulation (the tallest and among the oldest of the 12 patients enrolled and had the lowest baseline 6MWT values) [11, 13]. The severe deviation from normality due to their extreme values placed them in an “outliers” category justifying exclusion from the early treatment group.…”

Section: Gene Repair Through Mutation-specific Therapies In Dmd (Non-mentioning

confidence: 99%

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

Al-Zaidy¹,

Rodino‐Klapac²,

Mendell³

2014

Pediatric Neurology

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Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. While corticosteroids and/or supportive treatments remain standard of care for Duchenne muscular dystrophy (DMD), loss of ambulation, respiratory failure and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight therapeutic progress with emphasis on evolving pre-clinical data and our own experience in completed clinical trials, and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field.

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Section: Gene Repair Through Mutation-specific Therapies In Dmd (Non-mentioning

confidence: 99%

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

Al-Zaidy¹,

Rodino‐Klapac²,

Mendell³

2014

Pediatric Neurology

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“…The main objective of PT is the prevention of hypotrophy associated with contractures and bone deformities [8]. However, PT approaches have yielded controversial recommendations [9] and there is no consensus regarding the type and intensity of PT [10].…”

Section: Introductionmentioning

confidence: 99%

Motor Physical Therapy Affects Muscle Collagen Type I and Decreases Gait Speed in Dystrophin-Deficient Dogs

et al. 2014

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Golden Retriever Muscular Dystrophy (GRMD) is a dystrophin-deficient canine model genetically homologous to Duchenne Muscular Dystrophy (DMD) in humans. Muscular fibrosis secondary to cycles of degeneration/regeneration of dystrophic muscle tissue and muscular weakness leads to biomechanical adaptation that impairs the quality of gait. Physical therapy (PT) is one of the supportive therapies available for DMD, however, motor PT approaches have controversial recommendations and there is no consensus regarding the type and intensity of physical therapy. In this study we investigated the effect of physical therapy on gait biomechanics and muscular collagen deposition types I and III in dystrophin-deficient dogs. Two dystrophic dogs (treated dogs-TD) underwent a PT protocol of active walking exercise, 3×/week, 40 minutes/day, 12 weeks. Two dystrophic control dogs (CD) maintained their routine of activities of daily living. At t0 (pre) and t1 (post-physical therapy), collagen type I and III were assessed by immunohistochemistry and gait biomechanics were analyzed. Angular displacement of shoulder, elbow, carpal, hip, stifle and tarsal joint and vertical (Fy), mediolateral (Fz) and craniocaudal (Fx) ground reaction forces (GRF) were assessed. Wilcoxon test was used to verify the difference of biomechanical variables between t0 and t1, considering p<.05. Type I collagen of endomysium suffered the influence of PT, as well as gait speed that had decreased from t0 to t1 (p<.000). The PT protocol employed accelerates morphological alterations on dystrophic muscle and promotes a slower velocity of gait. Control dogs which maintained their routine of activities of daily living seem to have found a better balance between movement and preservation of motor function.

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“…Due weakening of respiratory muscle, these patients are unable to generate respiratory pressure (maximal inspiratory pressure and maximal expiratory pressure), and the peak expiratory flow is reduced. Thus, all of these factors lead to the premature death of DMD patients [3,7,8]. The main failure of muscles involved in breathing occurs in the diaphragm.…”

Section: Introductionmentioning

confidence: 99%

Muscle reorganisation through local injection of stem cells in the diaphragm of mdx mice

et al. 2012

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BackgroundThe diaphragm is the major respiratory muscle affected by Duchenne muscular dystrophy (DMD) and is responsible for causing 80% of deaths. The use of mechanical forces that act on the body or intermittent pressure on the airways improves the quality of life of patients but does not prevent the progression of respiratory failure. Thus, diseases that require tissue repair, such as DMD, represent a group of pathologies that have great potential for cell therapy. The application of stem cells directly into the diaphragm instead of systemic application can reduce cell migration to other affected areas and increase the chances of muscle reorganisation. The mdx mouse is a suitable animal model for this research because its diaphragmatic phenotype is similar to human DMD. Therefore, the aim of this study was to assess the potential cell implantation in the diaphragm muscle after the xenotransplantation of stem cells.MethodsA total of 9 mice, including 3 control BALB/Cmice, 3 5-month-old mdx mice without stem cell injections and 3 mdx mice injected with stem cells, were used. The animals injected with stem cells underwent laparoscopy so that stem cells from GFP-labelled rabbit olfactory epithelium could be locally injected into the diaphragm muscle. After 8 days, all animals were euthanised, and the diaphragm muscle was dissected and subjected to histological and immunohistochemical analyses.ResultsBoth the fresh diaphragm tissue and immunohistochemical analyses showed immunopositive GFP labelling of some of the cells and immunonegativity of myoblast bundles. In the histological analysis, we observed a reduction in the inflammatory infiltrate as well as the presence of a few peripheral nuclei and myoblast bundles.ConclusionWe were able to implant stem cells into the diaphragm via local injection, which promoted moderate muscle reorganisation. The presence of myoblast bundles cannot be attributed to stem cell incorporation because there was no immunopositive labelling in this structure. It is believed that the formation of the bundles may have been stimulated by cellular signalling mechanisms that have not yet been elucidated.

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Therapeutics in Duchenne muscular dystrophy

Cited by 41 publications

References 99 publications

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

Motor Physical Therapy Affects Muscle Collagen Type I and Decreases Gait Speed in Dystrophin-Deficient Dogs

Muscle reorganisation through local injection of stem cells in the diaphragm of mdx mice

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