Truncated dystrophins reduce muscle stiffness in the extensor digitorum longus muscle of mdx mice

Muscle stiffness is a major clinical feature in Duchenne muscular dystrophy (DMD). DMD is the most common lethal inherited muscle-wasting disease in boys, and it is caused by the lack of the dystrophin protein. We recently showed that the extensor digitorum longus (EDL) muscle of mdx mice (a DMD mouse model) exhibits disease-associated muscle stiffness. Truncated micro- and mini-dystrophins are the leading candidates for DMD gene therapy. Unfortunately, it has never been clear whether these truncated genes can mitigate muscle stiffness. To address this question, we examined the passive properties of the EDL muscle in transgenic mdx mice that expressed a representative mini- or micro-gene (H2-R15, R2-15/R18-23/C, or R4-23/C). The passive properties were measured at the ages of 6 and 20 mo and compared with those of age-matched wild-type and mdx mice. Despite significant truncation of the gene, surprisingly, the elastic and viscous properties were completely restored to the wild-type level in every transgenic strain we examined. Our results demonstrated for the first time that truncated dystrophin genes may effectively treat muscle stiffness in DMD.
Source: Journal of Applied Physiology - Category: Physiology Authors: Tags: ARTICLES Source Type: research

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Basel, 24 September 2021 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced data from across its growing neuromuscular portfolio at the World Muscle Society (WMS) Virtual Congress 20 – 24 September 2021. The presentations included additional results from the RAINBOWFISH study, evaluating the efficacy and safety of Evrysdi® (risdiplam) in babies with pre-symptomatic spinal muscular atrophy (SMA) from birth to six weeks of age and data supporting the continued clinical investig ation of gene therapy, SRP-9001, in Duchenne muscular dystrophy (DMD).“These new data for Evrysdi may help extend the potential ben...
Source: Roche Media News - Category: Pharmaceuticals Source Type: news
Human Gene Therapy,Volume 32, Issue 17-18, Page 872-874, September 2021.
Source: Human Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research
Funded in 2015, the DMD Hub, a collaboration between Duchenne UK and the two UK neuromuscular centres of excellence, is an established network of Duchenne muscular dystrophy (DMD) clinical trial sites in the UK ( With the arrival of advanced therapy trials for DMD, the DMD Hub is supporting the neuromuscular community to facilitate the setting up and running these trials in the UK. In November 2019, the DMD Hub held the first gene therapy meeting with over 100 key stakeholders including clinical experts, patient representatives, industry, regulators and payers to discuss existing barriers to gene therapy ac...
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Gene transfer therapy using systemic adeno-associated virus (AAV) delivery is being studied extensively for the treatment of monogenic diseases, such as Duchenne muscular dystrophy. Gene therapies are advancing rapidly, and it is crucial to optimize safety and efficacy as well as dosing of individuals with pre-existing antibodies against the vectors used for delivery. This nonhuman primate (NHP) study investigated the impact of various immunosuppression strategies on the safety and efficacy of gene transfer therapy and analyzed the safety and efficacy of therapeutic plasma exchange (TPE) as a potential pretreatment for ind...
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Duchenne muscular dystrophy (DMD) is an inherited and lethal disease leading to the lack of expression of dystrophin and muscle degeneration for which there is no curative treatment. Current life expectancy of DMD patients is 20 to 40 years with final cardio-respiratory complications. Clinical trials are ongoing using rAAV-microdystrophin (rAAV-MD) gene therapy. The aim being a shift from DMD toward a milder dystrophinopathy, the Becker muscular dystrophy (BMD). However, BMD patients still exhibit muscle decline and die before the age of 60.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive neuromuscular disorder, characterized by progressive muscle degeneration and premature death. DMD is caused by mutations in the DMD gene, leading to a severe reduction or absence of the protein dystrophin. Multiple therapeutic strategies, including gene therapy, aim to restore a functional dystrophin (mini-dystrophin) protein to muscle cells. The ability to accurately quantify dystrophin/mini-dystrophin is essential in determining the level of gene transduction.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
The field of gene therapy for Duchenne muscular dystrophy (DMD) has been very active in the past few years with multiple clinical trials going on. The large size of the disease causal gene DMD presents a challenge for AAV gene therapy as the cDNA of dystrophin is 14 kb, well over the carrying capacity of AAV. Thus, different AAV-microdystrophins (truncated forms of dystrophin) has been the main form of gene therapy for DMD in clinical development. While the trials are showing promising results, the limited transgene size and threat of anti-dystrophin immune response indicate the necessity to explore other strategies.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
CONCLUSION: These findings might serve as a rationale to fine-tune a disease-specific immunomodulatory regimen, particularly relevant in view of the rapid development of gene therapy for sarcoglycanopathies.PMID:34281632 | DOI:10.5414/NP301393
Source: Clinical Neuropathology - Category: Pathology Authors: Source Type: research
In conclusion, our study demonstrated that elevated cumulative SBP or DBP was independently associated with increased risk of CVD in the Chinese population. Among participants with 15-year cumulative BP levels higher than the median, that is, 1970.8/1239.9 mmHg-year for cumulative SBP/DBP, which was equivalent to maintaining SBP/DBP level higher than 131/83 mmHg in 15 years, the CVD risk would increase significantly irrespective of whether or not the BP measurements at one examination was high. Our findings emphasize the importance of cumulative BP level in identifying individuals with high risk of CVD in the future. ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Upregulation of telomerase expression and, separately, follistatin expression have been shown to extend life in mice. In recent news, researchers report a novel approach to delivering these two genes via gene therapy, making use of cytomegalovirus (CMV) as a vector. CMV is actually a major threat to human health, and might be responsible for a great deal of the age-related decline of the immune system. Near everyone is infected by the time old age rolls around. Nonetheless, one can develop viral vectors in which replication (and thus any threat of infection) is disabled, and these are widely used as tools in research and d...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
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