Genome Editing Gene Therapy for Duchenne Muscular Dystrophy

Hotta, Akitsu

doi:10.3233/jnd-150116

Cited by 14 publications

(9 citation statements)

References 98 publications

(60 reference statements)

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“…The strategies of gene therapy have been evolving over the past few years to restore dystrophin expression [88]. In gene augmentation approaches, transduction efficiency is critical problem due to the large size of the dystrophin cDNA.…”

Section: Utilized and Future Treatment Options For Heart Disease In Dmdmentioning

confidence: 99%

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The multifaceted view of heart problem in Duchenne muscular dystrophy

Florczyk-Soluch

Polak

Dulak

2021

Cell. Mol. Life Sci.

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Dystrophin is a large protein serving as local scaffolding repetitively bridging cytoskeleton and the outside of striated muscle cell. As such dystrophin is a critical brick primarily in dystrophin-associated protein complex (DAGC) and in a larger submembranous unit, costamere. Accordingly, the lack of functional dystrophin laying at the root of Duchenne muscular dystrophy (DMD) drives sarcolemma instability. From this point on, the cascade inevitably leading to the death of myocyte begins. In cardiomyocytes, intracellular calcium overload and related mitochondrial-mediated cell death mainly contribute to myocardial dysfunction and dilation while other protein dysregulation and/or mislocalization may affect electrical conduction system and favor arrhythmogenesis. Although clinically DMD manifests as progressive muscle weakness and skeletal muscle symptoms define characteristic of DMD, it is the heart problem the biggest challenge that most often develop in the form of dilated cardiomyopathy (DCM). Current standards of treatment and recent progress in respiratory care, introduced in most settings in the 1990s, have improved quality of life and median life expectancy to 4th decade of patient’s age. At the same time, cardiac causes of death related to DMD increases. Despite preventive and palliative cardiac treatments available, the prognoses remain poor. Direct therapeutic targeting of dystrophin deficiency is critical, however, hindered by the large size of the dystrophin cDNA and/or stochastic, often extensive genetic changes in DMD gene. The correlation between cardiac involvement and mutations affecting specific dystrophin isoforms, may provide a mutation-specific cardiac management and novel therapeutic approaches for patients with CM. Nonetheless, the successful cardiac treatment poses a big challenge and may require combined therapy to combat dystrophin deficiency and its after-effects (critical in DMD pathogenesis). This review locates the multifaceted heart problem in the course of DMD, balancing the insights into basic science, translational efforts and clinical manifestation of dystrophic heart disease.

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Section: Utilized and Future Treatment Options For Heart Disease In Dmdmentioning

confidence: 99%

“…The ex vivo gene therapy approach (i.e. testing cells isolated from patients) sets a rational direction to pre-define the success of gene correction and estimate off-target mutagenesis [88].…”

Section: Utilized and Future Treatment Options For Heart Disease In Dmdmentioning

confidence: 99%

The multifaceted view of heart problem in Duchenne muscular dystrophy

Florczyk-Soluch

Polak

Dulak

2021

Cell. Mol. Life Sci.

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“…These clones provide a useful material for investigation of different aspects of DMD biology such as metabolism, gene expression, chromatin organization and membrane changes or for screening of therapeutic strategies in complement with the known animal models. The information for each patient allows choice of the clones depending on clinical features, and patient genotyping will be essential for the design of exon skipping strategies such as the recent experiments using CRISPR-Cas9ti edit the DMD gene [ 43 , 44 ]. Moreover, working with several clones from the same patients avoids bias due to the insertion sites of the immortalization genes.…”

Section: Discussionmentioning

confidence: 99%

Derivation and Characterization of Immortalized Human Muscle Satellite Cell Clones from Muscular Dystrophy Patients and Healthy Individuals

Massenet

Gitiaux

Magnan

et al. 2020

Cells

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In Duchenne muscular dystrophy (DMD) patients, absence of dystrophin causes muscle wasting by impacting both the myofiber integrity and the properties of muscle stem cells (MuSCs). Investigation of DMD encompasses the use of MuSCs issued from human skeletal muscle. However, DMD-derived MuSC usage is restricted by the limited number of divisions that human MuSCs can undertake in vitro before losing their myogenic characteristics and by the scarcity of human material available from DMD muscle. To overcome these limitations, immortalization of MuSCs appears as a strategy. Here, we used CDK4/hTERT expression in primary MuSCs and we derived MuSC clones from a series of clinically and genetically characterized patients, including eight DMD patients with various mutations, four congenital muscular dystrophies and three age-matched control muscles. Immortalized cultures were sorted into single cells and expanded as clones into homogeneous populations. Myogenic characteristics and differentiation potential were tested for each clone. Finally, we screened various promoters to identify the preferred gene regulatory unit that should be used to ensure stable expression in the human MuSC clones. The 38 clonal immortalized myogenic cell clones provide a large collection of controls and DMD clones with various genetic defects and are available to the academic community.

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“…There are mainly four approaches that have been demonstrated to restore the open reading frame of dystrophin transcripts by genomic editing with CRISPR Cas9: (i) exon skipping by splicing acceptor disruption, (ii) exon deletion, (iii) NHEJ mediated frame shift, and (iv) exogenous exon knock-in [ 46 ] ( Figure 1 ). The use of each approach can be catered to the type of DMD mutation to be targeted ( Table 2 ).…”

Section: How Can Crispr Cas9 Be Applied To Dmd?mentioning

confidence: 99%

Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

Gee

Hotta

2017

Stem Cells International

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In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic.

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Genome Editing Gene Therapy for Duchenne Muscular Dystrophy

Cited by 14 publications

References 98 publications

The multifaceted view of heart problem in Duchenne muscular dystrophy

The multifaceted view of heart problem in Duchenne muscular dystrophy

Derivation and Characterization of Immortalized Human Muscle Satellite Cell Clones from Muscular Dystrophy Patients and Healthy Individuals

Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy

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