Preprint Review Version 1 This version is not peer-reviewed

Methods of CRISPR/Cas9 Exon Skipping for Duchenne Muscular Dystrophy

Version 1 : Received: 31 October 2018 / Approved: 2 November 2018 / Online: 2 November 2018 (05:14:23 CET)

A peer-reviewed article of this Preprint also exists.

Lim, K.R.Q.; Yoon, C.; Yokota, T. Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. J. Pers. Med. 2018, 8, 38. Lim, K.R.Q.; Yoon, C.; Yokota, T. Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. J. Pers. Med. 2018, 8, 38.

Journal reference: J. Pers. Med. 2018, 8, 38
DOI: 10.3390/jpm8040038

Abstract

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein which leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.

Subject Areas

Duchenne muscular dystrophy (DMD); CRISPR/Cas9; exon skipping therapy; gene editing; human induced pluripotent stem cells (hiPSCs); immortalized patient muscle cells; mdx mice; humanized dystrophic mouse models; deltaE50-MD dog model

Comments (1)

Comment 1
Received: 24 January 2019
Commenter: Martin L. Nelwan (Click to see Publons profile: )
The commenter has declared there is no conflict of interests.
Comment: In this article, the authors described the Duchene muscular dystrophy (DMD) and its genetic causes. In addition, the CRISPR/Cas9 system, as well as its potential gene therapy in the treatment of DMD patients, was discussed. It does discuss an important issue of the CRISPR/Cas9 system to treat the disorder. For example, the authors described the classical exon skipping (CES) and direct exon skipping (DES) strategies to treat the DMD disorder. It is an interesting article. However, the writing style of this manuscript still needs corrections. There are many long sentences and passive voice throughout the article.

For example, the authors stated:

“As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss dystrophin protein which leads to decreased muscle membrane integrity, which increases susceptibility to degeneration.” This is a long sentence (30 words) and in a passive voice. I suggest: “As a result of mutations that interrupt the reading frame of the dystrophin (DMD) gene, loss of dystrophin protein characterized DMD which leads to decreased muscle membrane integrity. It increases susceptibility to degeneration.”

“Unlike AOs however, a distinct advantage of using CRISPR systems for DMD therapy is that they induce permanent corrections to the DMD gene and thus would not require repetitive and extensive durations of treatment.” It is a long sentence (34 words). Split it into two sentences.

Others:

In my opinion, the author should discuss the DMD gene and mutations in a section. For example, the section could include Genes in DMD, The DMD gene, and Mutations in the DMD gene. It is my suggestions. The authors can use their wording themselves and I think they can do that easily.
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