Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial

Kirschner, Janbernd; Scheßl, J.; Schara, Ulrike; Reitter, B.; Stettner, Georg M.; Hobbiebrunken, Elke; Wilichowski, Ekkehard; Bernert, G.; Weiss, Simone; Stehling, Florian; Wiegand, Gert; Müller‐Felber, Wolfgang; Thiele, Simone; Grieben, Ulrike; Hagen, Maja von der; Lütschg, Jürg; Schmoor, Claudia; Ihorst, Gabriele; Korinthenberg, Rudolf

doi:10.1016/s1474-4422(10)70196-4

Cited by 55 publications

(39 citation statements)

References 25 publications

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“…Consistent with our published (23) and current observations in KO mice ( Fig. 1 (32)(33)(34). Second, GC therapy provides benefit in DMD patients even when administered via low or intermittent dosing schemes that do not provide a potent and sustained antiinflammatory effect (15).…”

Section: Klf15 Issupporting

confidence: 90%

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Morrison‐Nozik

Anand

Zhu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.skeletal muscle metabolism | glucocorticoid | exercise | Duchenne muscular dystrophy | steroid hormone nuclear receptor

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Section: Klf15 Issupporting

confidence: 90%

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Morrison‐Nozik

Anand

Zhu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies characterizing the functional decline and rate of progression of neuromuscular disorders such as amyotrophic lateral sclerosis, 27 Duchenne muscular dystrophy, 28 and Charcot-Marie-Tooth disease 29 depend on hand-held dynamometry to capture and track relevant changes in muscle strength. Access to reliable and expansive normative reference values and associated ageand sex-matched z scores are necessary to accurately and precisely quantify response to new interventions and to establish minimum clinically important differences.…”

Section: Resultsmentioning

confidence: 99%

Normative reference values for strength and flexibility of 1,000 children and adults

et al. 2017

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Objective: To establish reference values for isometric strength of 12 muscle groups and flexibility of 13 joint movements in 1,000 children and adults and investigate the influence of demographic and anthropometric factors.Methods: A standardized reliable protocol of hand-held and fixed dynamometry for isometric strength of ankle, knee, hip, elbow, and shoulder musculature as well as goniometry for flexibility of the ankle, knee, hip, elbow, shoulder, and cervical spine was performed in an observational study investigating 1,000 healthy male and female participants aged 3-101 years. Correlation and multiple regression analyses were performed to identify factors independently associated with strength and flexibility of children, adolescents, adults, and older adults. Results:Normative reference values of 25 strength and flexibility measures were generated.Strong linear correlations between age and strength were identified in the first 2 decades of life. Muscle strength significantly decreased with age in older adults. Regression modeling identified increasing height as the most significant predictor of strength in children, higher body mass in adolescents, and male sex in adults and older adults. Joint flexibility gradually decreased with age, with little sex difference. Waist circumference was a significant predictor of variability in joint flexibility in adolescents, adults, and older adults. Conclusions:Reference values and associated age-and sex-stratified z scores generated from this study can be used to determine the presence and extent of impairments associated with neuromuscular and other neurologic disorders, monitor disease progression over time in natural history studies, and evaluate the effect of new treatments in clinical trials. Neurology ® 2017;88:36-43Meaningful, reliable, and sensitive outcome measures are required to monitor treatment and progression of neuromuscular and other neurologic disorders. While there have been substantial advances in the understanding of the pathogenesis and natural history of many neuromuscular disorders, the identification and development of new outcome measures that best reflect the efficacy of specific treatments have not advanced at the same rate. 1 Establishing valid and responsive outcome measures is a priority for the field. 2 To assist in the development of new outcome measures, normative reference values generated from large populations across the lifespan using standardized methods are required. Normative reference values can be utilized to generate z scores, which can be used in multicenter studies to improve outcome measure precision and responsiveness.Muscle weakness and joint contractures predispose to numerous pathologies requiring intervention. Reference data play an important role in identifying and quantifying these impairments and evaluating the effectiveness of interventions. Currently, few comprehensive datasets detail the normal variation of active range of motion in healthy individuals and are limited by the number of joints assessed, 3...

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“…220 This result was reflected in DMD clinical trials where a small study reported improvements in muscle-force generation, 221 but a following, larger randomized trial illustrated little benefit. 222 To circumvent the effect of long-term CsA treatment on both the immune system and calcineurin signaling, use of a nonimmunosuppressing CsA analog (Debio-025) was recently shown to enhance MPTP blockade over CsA or prednisolone in mdx, and is under assessment for other muscular dystrophies (reviewed in Fairclough et al). 162 Necrosis Dysregulation of the NO/cyclic guanosine monophosphate (cGMP) pathway has been implicated in the loss of contractile performance and sarcolemmal integrity in dystrophic muscle.…”

Section: Dovepressmentioning

confidence: 99%

Recent advances in Duchenne muscular dystrophy

Perkins

Davies

2012

DNND

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Duchenne muscular dystrophy (DMD), an allelic X-linked progressive musclewasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene-and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene-and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.

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Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial

Cited by 55 publications

References 25 publications

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Normative reference values for strength and flexibility of 1,000 children and adults

Recent advances in Duchenne muscular dystrophy

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