CRISPR gene-editing technology creates precise and permanent modifications to DNA. It has significantly advanced our ability to generate animal disease models for use in biomedical research and... Show moreCRISPR gene-editing technology creates precise and permanent modifications to DNA. It has significantly advanced our ability to generate animal disease models for use in biomedical research and also has potential to revolutionize the treatment of genetic disorders. Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disease that could potentially benefit from the development of CRISPR therapy. It is commonly associated with mutations that disrupt the reading frame of the DMD gene that encodes dystrophin, an essential scaffolding protein that stabilizes striated muscles and protects them from contractile-induced damage. CRISPR enables the rapid generation of various animal models harboring mutations that closely simulates the wide variety of mutations observed in DMD patients. These models provide a platform for the testing of sequence-specific interventions like CRISPR therapy that aim to reframe or skip DMD mutations to restore functional dystrophin expression. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Show less
Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo... Show moreUsing external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean delta NSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0-0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ANSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD. (C) 2022 The Authors. Published by Elsevier B.V. Show less
We aimed to investigate BMI-z course in patients with Duchenne muscular dystrophy (DMD) during transition to loss of ambulation, and to explore the contribution of caloric intake and corticosteroid... Show moreWe aimed to investigate BMI-z course in patients with Duchenne muscular dystrophy (DMD) during transition to loss of ambulation, and to explore the contribution of caloric intake and corticosteroid use. A retrospective multicenter longitudinal study was conducted. First, analyses of characteristics at first visit were carried out. Second, discontinuous change models were fitted to explore associations between BMI-z, loss of ambulation, caloric intake and corticosteroid use. 790 visits of 159 patients were collected. Cross sectional first visit analyses showed the presence of overweight and obesity was 44% in the ambulant group and 51% in the non-ambulant group. In the non-ambulatory group, exceeding the recommended caloric intake was associated with higher BMI-z scores (r 0.36, p = 0.04). Patients who were using corticosteroids had significantly higher BMI-z scores compared with patients not using corticosteroids (1.06 and 0.51 respectively, p = 0.02). Longitudinal analyses on patients ambulant at first visit showed an increase in BMI-z score during transition to the non-ambulatory phase. Caloric intake and corticosteroid use were not associated with BMI-z. Transition to the non-ambulatory phase may be crucial in the development of excessive weight gain. Early measures - starting before this time frame - may contribute to reduce development of obesity. (c) 2022 The Author(s). Published by Elsevier B.V. Show less
The article of Lopez et al describes the use of a multi-parametric MR approach to study muscle T-2 relaxation times and P-31-MRS indices of energetics and sarcolemma integrity in a mouse model of... Show moreThe article of Lopez et al describes the use of a multi-parametric MR approach to study muscle T-2 relaxation times and P-31-MRS indices of energetics and sarcolemma integrity in a mouse model of DMD, the mdx mouse. Muscular dystrophies have a multi-factorial disease cascade, and there are several MR methods used to assess these. Aspects that reflect disease progression are outlined on the left, while features that are more related to disease activity are outlined on the right. Show less
