Efficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS.
Efficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS.
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DOI：
10.1038/s42003-021-01942-4
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发表时间：
2021-03-25
影响因子：
5.9
通讯作者：
Siddique T
中科院分区：
文献类型：
--
作者：
Deng HX;Zhai H;Shi Y;Liu G;Lowry J;Liu B;Ryan ÉB;Yan J;Yang Y;Zhang N;Yang Z;Liu E;Ma YC;Siddique T
CRISPR/Cas9介导的基因组编辑为治疗开发提供了潜力。有效性和长期安全性是临床前研究中仍需充分解决的主要问题。在这里，我们展示了CRISPR/Cas9介导的基因组编辑在两种不同的SOD 1-肌萎缩侧索硬化（ALS）转基因小鼠模型中预防了ALS样疾病和病理的发展。疾病连锁转基因被有效编辑，具有罕见的脱靶编辑事件。我们观察到频繁的大DNA缺失，范围从几百到几千个碱基对。我们确定，这些大的缺失介导的Alu元素中的近似相同的序列。在这些基因组编辑的小鼠中，没有观察到超过2岁的其他疾病的证据。我们的数据为CRISPR/Cas9治疗方法的有效性和长期安全性提供了临床前证据。此外，接近相同序列介导的重组的分子机制提供了优化治疗靶向设计的机制信息，并避免或最大限度地减少意外和潜在有害的重组事件。Deng等人评估了CRISPR/Cas9介导的基因组编辑在两种肌萎缩侧索硬化症（ALS）转基因小鼠模型中长达2年的影响。他们发现，基因组编辑阻止了ALS样病理的发展，没有任何明显的副作用，这为CRISPR/Cas9治疗方法的有效性和长期安全性提供了临床前证据。
CRISPR/Cas9-mediated genome editing provides potential for therapeutic development. Efficacy and long-term safety represent major concerns that remain to be adequately addressed in preclinical studies. Here we show that CRISPR/Cas9-mediated genome editing in two distinct SOD1-amyotrophic lateral sclerosis (ALS) transgenic mouse models prevented the development of ALS-like disease and pathology. The disease-linked transgene was effectively edited, with rare off-target editing events. We observed frequent large DNA deletions, ranging from a few hundred to several thousand base pairs. We determined that these large deletions were mediated by proximate identical sequences in Alu elements. No evidence of other diseases was observed beyond 2 years of age in these genome edited mice. Our data provide preclinical evidence of the efficacy and long-term safety of the CRISPR/Cas9 therapeutic approach. Moreover, the molecular mechanism of proximate identical sequences-mediated recombination provides mechanistic information to optimize therapeutic targeting design, and to avoid or minimize unintended and potentially deleterious recombination events. Deng et al. assess the effects of CRISPR/Cas9-mediated genome editing in two transgenic mouse models of amyotrophic lateral sclerosis (ALS) for up to 2 years. They find that the genomic editing prevented the development of ALS-like pathology without any notable side-effects, which provides preclinical evidence of the effectiveness and long-term safety of the CRISPR/Cas9 therapeutic approach.
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DOI：
10.1016/j.tig.2008.08.007
发表时间：
2008-11
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McVey M;Lee SE
通讯作者：
Lee SE
影响因子：
13.6
作者：
Gaj T;Ojala DS;Ekman FK;Byrne LC;Limsirichai P;Schaffer DV
通讯作者：
Schaffer DV
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
12.4
作者：
Foust, Kevin D.;Salazar, Desiree L.;Kaspar, Brian K.
通讯作者：
Kaspar, Brian K.