Abstract:Dystrophin deficiency causes contraction-induced injury and damage to the muscle fiber, resulting in sustained increase in intracellular calcium levels, activation of calcium-dependent proteases and cell death. It is known that the Ryanodine receptor (RyR1) on the sarcoplasmic reticular (SR) membrane controls calcium release. Dantrolene, an FDA approved skeletal muscle relaxant, inhibits the release of calcium from the SR during excitation-contraction and suppresses uncontrolled calcium release by directly act… Show more
“…In keeping with a previous report, mdx treatment with 40 mg/kg dantrolene alone lowers CK to some extent but not to the same degree as treatment with dantrolene and e23AON combined. 31 However, the high degree of rescue induced by each dantrolene and phosphorodiamidate morpholino oligomer (PMO) alone precludes distinguishing between a synergistic versus additive effect. Figure 7 Creatine Kinase Reduction Is Boosted with Dantrolene/e23AON Combination Therapy (A) A reduction in creatine kinase levels with the addition of dantrolene in mice receiving 0, 10, and 50 mg/kg e23AON/dantrolene combination.…”
Section: Resultsmentioning
confidence: 99%
“…We demonstrated reduced CK levels in mdx mice treated with dantrolene alone, but observed no effect on any other measures of mdx histopathology or exon skipping in the absence of e23AON, consistent with published data. 31 , 60 In one published study in mdx mice, 6-week 40 mg/kg dantrolene treatment reduced both CK levels and some, but not all, measures of strength, despite no observed effect on histopathology. 31 It is reasonable to anticipate that if there is a beneficial effect in humans, chronic administration will be necessary.…”
Section: Discussionmentioning
confidence: 99%
“… 31 , 60 In one published study in mdx mice, 6-week 40 mg/kg dantrolene treatment reduced both CK levels and some, but not all, measures of strength, despite no observed effect on histopathology. 31 It is reasonable to anticipate that if there is a beneficial effect in humans, chronic administration will be necessary. Because we observed skip boosting activity at doses in the low range used chronically for spasticity and higher dosing has been reported to induce mild muscle weakness in some instances, 61 it would be prudent to perform a dose-ranging trial in humans prior to routine use of combination therapy for DMD.…”
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD âexon skippingâ uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies. Here, we assess the effect of dantrolene/AON combination on DMD exon-23 skipping over long-term mdx treatment under conditions that better approximate potential human dosing. To evaluate the dantrolene/AON combination treatment effect on dystrophin induction, we assayed three AON doses, with and without oral dantrolene, to assess multiple outcomes across different muscles. Meta-analyses of the results of statistical tests from both the quadriceps and diaphragm assessing contributions of dantrolene beyond AON, across all AON treatment groups, provide strong evidence that dantrolene modestly boosts exon skipping and dystrophin rescue while reducing muscle pathology in mdx mice (p < 0.0087). These findings support a trial of combination dantrolene/AON to increase exon-skipping efficacy and highlight the value of combinatorial approaches and Food and Drug Administration (FDA) drug re-purposing for discovery of unsuspected therapeutic application and rapid translation.
“…In keeping with a previous report, mdx treatment with 40 mg/kg dantrolene alone lowers CK to some extent but not to the same degree as treatment with dantrolene and e23AON combined. 31 However, the high degree of rescue induced by each dantrolene and phosphorodiamidate morpholino oligomer (PMO) alone precludes distinguishing between a synergistic versus additive effect. Figure 7 Creatine Kinase Reduction Is Boosted with Dantrolene/e23AON Combination Therapy (A) A reduction in creatine kinase levels with the addition of dantrolene in mice receiving 0, 10, and 50 mg/kg e23AON/dantrolene combination.…”
Section: Resultsmentioning
confidence: 99%
“…We demonstrated reduced CK levels in mdx mice treated with dantrolene alone, but observed no effect on any other measures of mdx histopathology or exon skipping in the absence of e23AON, consistent with published data. 31 , 60 In one published study in mdx mice, 6-week 40 mg/kg dantrolene treatment reduced both CK levels and some, but not all, measures of strength, despite no observed effect on histopathology. 31 It is reasonable to anticipate that if there is a beneficial effect in humans, chronic administration will be necessary.…”
Section: Discussionmentioning
confidence: 99%
“… 31 , 60 In one published study in mdx mice, 6-week 40 mg/kg dantrolene treatment reduced both CK levels and some, but not all, measures of strength, despite no observed effect on histopathology. 31 It is reasonable to anticipate that if there is a beneficial effect in humans, chronic administration will be necessary. Because we observed skip boosting activity at doses in the low range used chronically for spasticity and higher dosing has been reported to induce mild muscle weakness in some instances, 61 it would be prudent to perform a dose-ranging trial in humans prior to routine use of combination therapy for DMD.…”
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD âexon skippingâ uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies. Here, we assess the effect of dantrolene/AON combination on DMD exon-23 skipping over long-term mdx treatment under conditions that better approximate potential human dosing. To evaluate the dantrolene/AON combination treatment effect on dystrophin induction, we assayed three AON doses, with and without oral dantrolene, to assess multiple outcomes across different muscles. Meta-analyses of the results of statistical tests from both the quadriceps and diaphragm assessing contributions of dantrolene beyond AON, across all AON treatment groups, provide strong evidence that dantrolene modestly boosts exon skipping and dystrophin rescue while reducing muscle pathology in mdx mice (p < 0.0087). These findings support a trial of combination dantrolene/AON to increase exon-skipping efficacy and highlight the value of combinatorial approaches and Food and Drug Administration (FDA) drug re-purposing for discovery of unsuspected therapeutic application and rapid translation.
“…Interestingly, treatment with S107, which inhibits Ca 2+ leakage from the SR by reducing the deletion of calstabin from the RyR, alleviates muscle weakness and the dystrophic phenotype. In relation to these results, treatment with nifedipine or dantrolene, an inhibitor of DHPR or the RyR, alleviates the phenotype of dystrophic muscle 77,78) . Furthermore, the overexpression of sarcoplasmic reticulum Ca 2+ ATPase1 (SERCA1), which is responsible for Ca 2+ uptake into the SR in ÎŽ-sarcoglycan-null mice, resulted in attenuation of the dystrophic phenotype 79) .…”
Section: Role Of Ca 2+ Signaling In Muscle Atrophymentioning
Skeletal muscle maintains an adequate volume that is commensurate with its surrounding environment. Although intracellular signaling molecules and pathways underlying the regulation of protein synthesis/degradation and subsequent muscle hypertrophy/atrophy are well studied, upstream regulators are largely unknown. In this review, we summarize the recent advances relating to the role of Ca 2+ signaling as an upstream regulator of intracellular signaling pathways that regulate muscle plasticity, suggesting a new therapeutic target to control muscle mass.
“…The screening performed by Kendall and colleagues using the BioMol library has led to the identification of a number of active compounds [ 80 ]. Among those, Dantrolene, a drug approved by the Food and Drug Administration (FDA), was selected as the lead compound despite not having the highest efficacy among the molecules identified, due to clinical studies conducted on DMD patients and animals models for DMD that showed modest, although detectable, improvements in muscle pathology [ 105 , 106 , 107 ]. Dantrolene is a muscle relaxant known to inhibit excitationâcontraction coupling in muscle, likely through its binding to the ryanodine receptor (RyR1) and by preventing the release of calcium from the sarcoplasmic reticulum.…”
Section: Hts Of Small Molecules That Enhance Skipping Of the Dystrmentioning
Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.
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