Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot

Wilton-Clark, Harry; Yokota, Toshifumi

doi:10.3390/genes13020257

Cited by 22 publications

(11 citation statements)

References 74 publications

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“…U7snRNA prevents the binding of splicing enzymes with pre-mRNA, which excludes the flanked exon from mature mRNA. The testing of this approach on mouse and human cells shows that completely excluding both copies of exon 2 leads to the synthesis of truncated but functionally active dystrophin [ 46 ]. Currently, three participants with confirmed duplication of exon 2 (NCT04240314) are undergoing trials [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Specificities of the DMD Gene Mutation Spectrum in Russian Patients

Zinina

Булах

Чухрова

et al. 2022

IJMS

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Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common form of muscular dystrophy, accounting for over 50% of all cases. In this regard, in Russia we carry out a program of selective screening for DMD/BMD, which mainly involves male patients. The main inclusion criteria are an increase in the level of creatine phosphokinase (>2000 U/L) or an established clinical diagnosis. At the first stage of screening, patients are scanned for extended deletions and duplications in the DMD gene using multiplex ligase-dependent probe amplification (MLPA SALSA P034 and P035 DMD probemix, MRC-Holland). The second stage is the search for small mutations using a custom NGS panel, which includes 31 genes responsible for various forms of limb-girdle muscular dystrophy. In a screening of 1025 families with a referral Duchenne/Becker diagnosis, pathogenic and likely pathogenic variants in the DMD gene were found in 788 families (in 76.9% of cases). In the current study, we analyzed the mutation spectrum of the DMD gene in Russian patients and noted certain differences between the examined cohort and the multi-ethnic cohort. The analysis of the DMD gene mutation spectrum is essential for patients with DMD/BMD because the exact mutation type determines the application of a specific therapeutic method.

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Section: Discussionmentioning

confidence: 99%

Specificities of the DMD Gene Mutation Spectrum in Russian Patients

Zinina

Булах

Чухрова

et al. 2022

IJMS

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“…This has greatly improved the chances of success for new drugs for NMDs in clinical trials and avoided initiation of trials for compounds that have limited preclinical efficiency. Unfortunately, despite these efforts, unforeseen events, such as recent patient deaths associated with AAV-based gene therapies for both X-linked myotubular myopathy and DMD, have occurred in clinical trials ( Wilton-Clark and Yokota, 2022 ). This underlines that, whereas model systems may guide clinical trial design, they are never fully predictive of the human disease, and new therapeutic approaches bring risks when they are first tested in humans.…”

Section: The Road To Therapy and Future Outlookmentioning

confidence: 99%

The predictive value of models of neuromuscular disorders to potentiate clinical translation

Putten

2022

Disease Models &Amp; Mechanisms

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Neuromuscular disorders (NMDs) are a heterogenous group of rare inherited diseases that compromise the function of peripheral nerves and/or muscles. With limited treatment options available, there is a growing need to design effective preclinical studies that can lead to greater success in clinical trials for novel therapeutics. Here, I discuss recent advances in modelling NMDs to improve preclinical studies as well as two articles from this issue that work in parallel to enable a deeper understanding of a particularly rare NMD, known as X-linked myotubular myopathy.

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“…The notion of miniaturized dystrophin was based on a Becker muscular dystrophy patient, who remained ambulatory for seven decades despite a deletion of nearly half of the DMD gene [ 28 ]. Recently, mini-dystrophin incorporating different spectrin repeats (SRs) and hinges ( Figure 1 ) delivered by different AAV serotypes are undergoing assessment of safety and efficacy in three simultaneous gene therapy trials ( Table 1 ) [ 29 ] sponsored by Sarepta Therapeutics, Pfizer, and Solid Biosciences.…”

Section: Clinical Development Of Systemic Aav-mediated Mini/micro-dys...mentioning

confidence: 99%

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy

Song

2022

Genes

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Gene therapy using the adeno-associated virus (rAAV) to deliver mini/micro- dystrophin is the current promising strategy for Duchenne Muscular Dystrophy (DMD). However, the further transformation of this strategy still faces many “bottlenecks”. Most gene therapies are only suitable for infants with strong muscle cell regeneration and immature immune system, and the treatment depends heavily on the high dose of rAAV. However, high-dose rAAV inevitably causes side effects such as immune response and acute liver toxicity. Therefore, how to reduce the degree of fibrosis and excessive immune response in older patients and uncouple the dependence association between therapeutic effect and high dose rAAV are crucial steps for the transformation of rAAV-based gene therapy. The article analyzes the latest research and finds that the application of utrophin, the homologous protein of dystrophin, could avoid the immune response associated with dystrophin, and the exploration of methods to improve the expression level of mini/micro-utrophin in striated muscle, combined with the novel MyoAAV with high efficiency and specific infection of striated muscle, is expected to achieve the same therapeutic efficacy under the condition of reducing the dose of rAAV. Furthermore, the delivery of allogeneic cardio sphere-derived cells (CDCs) with anti-inflammatory and anti-fibrotic characteristics combined with immune suppression can provide a continuous and appropriate “window period” for gene therapy. This strategy can expand the number of patients who could benefit from gene therapy.

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Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot

Cited by 22 publications

References 74 publications

Specificities of the DMD Gene Mutation Spectrum in Russian Patients

Specificities of the DMD Gene Mutation Spectrum in Russian Patients

The predictive value of models of neuromuscular disorders to potentiate clinical translation

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy

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