Genome Editing of Monogenic Neuromuscular Diseases

Long, Chengzu; Amoasii, Leonela; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1001/jamaneurol.2016.3388

Cited by 34 publications

(22 citation statements)

References 55 publications

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“…The widespread use of CRISPR/Cas9 for nuclear genome editing confirms the value of this technology (58,61), but it has yet to be applied to mtDNA. The challenge of the CRISPR/Cas9 system to prevent transmission of mitochondrial disease is that there is no evidence that the sgRNA species can cross the mitochondrial membrane, and there have been no reports of a successful application of this technique to correct mtDNA mutations.…”

Section: Potential Gene Therapy To Prevent Transmission Of Mitochondrmentioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

242

198

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Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.

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Section: Potential Gene Therapy To Prevent Transmission Of Mitochondrmentioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

242

198

View full text Add to dashboard Cite

show abstract

“…The chief concerns surrounding this approach are similar to the other proposed strategies: possible nonspecific/off-target effects and immunogenicity to either the genome editing components or delivery particles, particularly if a viral vector-mediated delivery system is used. In addition, perhaps 1 of the biggest challenges is distribution and ensuring the target tissue is reached, a problem highlighted by the first ASO clinical trial discussed above [143]. Nevertheless, in vitro genome editing studies in DM1 have been promising.…”

Section: Genome Editingmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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“…It induces double strand breaks (DSBs) which repair through non-homologous end-joining (NHEJ), or in the presence of a suitable DNA template, by homology-directed repair (HDR). The CRISPR-Cas9 system thus enables highly specific gene editing giving it great potential for correction of genetic (particularly monogenic) diseases 4,5 , or for revolutionising cell-based therapies. Genome editing of the germline in humans is obviously fraught with ethical considerations.…”

Section: Introductionmentioning

confidence: 99%