Delivery Aspects of CRISPR/Cas for in Vivo Genome Editing

Abstract:
Conspectus The discovery of CRISPR/Cas has revolutionized the field of genome editing. CRIPSR/Cas components are part of the bacterial immune system and are able to induce double-strand DNA breaks in the genome, which are resolved by endogenous DNA repair mechanisms. The most relevant of these are the error-prone nonhomologous end joining and homology directed repair pathways. The former can lead to gene knockout by introduction of insertions and deletions at the cut site, while the latter can be used for gene correction based on a provided repair template. In this Account, we focus on the delivery aspects of CRISPR/Cas for therapeutic applications in vivo. Safe and effective delivery of the CRISPR/Cas components into the nucleus of affected cells is essential for therapeutic gene editing. These components can be delivered in several formats, such as pDNA, viral vectors, or ribonuclear complexes. In the ideal case, the delivery system should address the current limitations of CRISPR gene editing, which are (1) lack of targeting specific tissues or cells, (2) the inability to enter cells, (3) activation of the immune system, and (4) off-target events. To circumvent most of these problems, initial therapeutic applications of CRISPR/Cas were performed on cells ex vivo via classical methods (e.g., microinjection or electroporation) and novel methods (e.g., TRIAMF and iTOP). Ideal candidates for such methods are, for example, hematopoietic cells, but not all tissue types are suited for ex vivo manipulation. For direct in vivo application, however, delivery systems are needed that can target the CRISPR/Cas components to specific tissues or cells in the human body, without causing immune activation or causing high frequencies of off-target effects. Viral systems have been used as a first resort to transduce cells in vivo. These systems suffer from problems related to packaging constraints, immunogenicity, and longevity of Cas expression, which favors off-target events. Viral vectors are as such not the best choice for direct in vivo delivery of CRISPR/Cas. Synthetic vectors can deliver nucleic acids as well, without the innate disadvantages of viral vectors. They can be classed into lipid, polymeric, and inorganic particles, all of which have been reported in the literature. The advantage of synthetic systems is that they can deliver the CRISPR/Cas system also as a preformed ribonucleoprotein complex. The transient nature of this approach favors low frequencies of off-target events and minimizes the window of immune activation. Moreover, from a pharmaceutical perspective, synthetic delivery systems are much easier to scale up for clinical use compared to viral vectors and can be chemically functionalized with ligands to obtain target cell specificity. The first preclinical results with lipid nanoparticles delivering CRISPR/Cas either as mRNA or ribonucleoproteins are very promising. The goal is translating these CRISPR/Cas therapeutics to a clinical setting as well. Taken together, these current trends seem to favor the use of sgRNA/Cas ribonucleoprotein complexes delivered in vivo by synthetic particles.
Author Listing： Danny Wilbie;Johanna Walther;Enrico Mastrobattista
Volume： 52
Pages： 1555 - 1564
DOI： 10.1021/acs.accounts.9b00106
Language： English
Journal： Accounts of Chemical Research

ACCOUNTS OF CHEMICAL RESEARCH

Acc. Chem. Res.

影响因子：16.4 是否综述期刊：是 是否OA：否 是否预警：不在预警名单内 发行时间：1968 ISSN：0001-4842 发刊频率：Monthly 收录数据库：SCIE/Scopus收录 出版国家/地区：UNITED STATES 出版社：American Chemical Society

期刊介绍

Accounts of Chemical Research 主要发表化学和生物化学领域内关于基础研究和应用的短小精悍、具有作者团队自己研究特色的述评文章，或者前瞻性观点。这些短综述都是基于作者自己实验室的过往研究，以便向读者完整介绍研究项目。期刊收录研究方向：化学，化学综合Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Visit the Accounts Special Issues page for listings, descriptions, and TOC's of all special issues.Beginning in 2008, Accounts of Chemical Research replaced their traditional article abstract with an article "Conspectus." These new entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article’s discoverability by search engines and the exposure for the research.

化学研究报告提供了简短，简洁和关键的文章，提供了化学和生物化学所有领域的基础研究和应用的易于阅读的概述。此外，《化学研究报告》还出版了专门针对异常活动和意义的单一问题的特刊。访问帐户特殊问题页面以获取所有特殊问题的列表，描述和目录。从2008年开始，化学研究帐户用文章 “Conspectus” 代替了传统的文章摘要。这些新条目概述了这项研究，使读者可以更仔细地了解文章的内容和意义。通过提供对文章内容的更详细描述，Conspectus增强了搜索引擎对文章的可发现性和对研究的了解。

年发文量 311
国人发稿量 102
国人发文占比 32.8%
自引率 0.6%
平均录取率 极难
平均审稿周期 一般,3-6周
版面费 -
偏重研究方向 化学-化学综合
期刊官网 https://pubs.acs.org/journal/achre4
投稿链接 https://acs.manuscriptcentral.com/acs

质量指标占比

研究类文章占比 OA被引用占比 撤稿占比 出版后修正文章占比
0.00% 12.32% 0.00% 0.90%

相关指数

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期刊预警不是论文评价，更不是否定预警期刊发表的每项成果。《国际期刊预警名单（试行）》旨在提醒科研人员审慎选择成果发表平台、提示出版机构强化期刊质量管理。

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具体而言，就是通过综合评判期刊载文量、作者国际化程度、拒稿率、论文处理费（APC）、期刊超越指数、自引率、撤稿信息等，找出那些具备风险特征、具有潜在质量问题的学术期刊。最后，依据各刊数据差异，将预警级别分为高、中、低三档，风险指数依次减弱。

《国际期刊预警名单（试行）》确定原则是客观、审慎、开放。期刊分区表团队期待与科研界、学术出版机构一起，夯实科学精神，打造气正风清的学术诚信环境！真诚欢迎各界就预警名单的分析维度、使用方案、值得关切的期刊等提出建议！

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分区表升级版（试行）旨在解决期刊学科体系划分与学科发展以及融合趋势的不相容问题。由于学科交叉在当代科研活动的趋势愈发显著，学科体系构建容易引发争议。为了打破学科体系给期刊评价带来的桎梏，“升级版方案”首先构建了论文层级的主题体系，然后分别计算每篇论文在所属主题的影响力，最后汇总各期刊每篇论文分值，得到“期刊超越指数”，作为分区依据。

分区表升级版（试行）的优势：一是论文层级的主题体系既能体现学科交叉特点，又可以精准揭示期刊载文的多学科性；二是采用“期刊超越指数”替代影响因子指标，解决了影响因子数学性质缺陷对评价结果的干扰。整体而言，分区表升级版（试行）突破了期刊评价中学科体系构建、评价指标选择等瓶颈问题，能够更为全面地揭示学术期刊的影响力，为科研评价“去四唯”提供解决思路。相关研究成果经过国际同行的认可，已经发表在科学计量学领域国际重要期刊。

《2019年中国科学院文献情报中心期刊分区表升级版（试行）》首次将社会科学引文数据库（SSCI）期刊纳入到分区评估中。升级版分区表（试行）设置了包括自然科学和社会科学在内的18个大类学科。基础版和升级版（试行）将过渡共存三年时间，推测在此期间各大高校和科研院所仍可能会以基础版为考核参考标准。 提示：中科院分区官方微信公众号“fenqubiao”仅提供基础版数据查询，暂无升级版数据，请注意区分。

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