Addressing challenges in the clinical applications associated with CRISPR/Cas9 technology and ethical questions to prevent its misuse.
Addressing challenges in the clinical applications associated with CRISPR/Cas9 technology and ethical questions to prevent its misuse.
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解决与 CRISPR/Cas9 技术相关的临床应用挑战和伦理问题，以防止其滥用。
DOI：
10.1007/s13238-017-0477-4
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发表时间：
2017-11
期刊：
影响因子：
21.1
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Kang XJ;Caparas CIN;Soh BS;Fan Y
最近发展起来的RNA引导的簇状规则间隔短回文重复序列(CRISPR)/CRISPR相关9(Cas9)核酸酶系统已经成为体细胞类型和生殖系模式生物基因组操作的一项宝贵技术。虽然人类胚胎基因编辑研究的前所未有的进步在下一代治疗学中具有巨大的潜力，但它引发了各种伦理问题，在转化为临床使用之前需要解决这些问题。在这里，我们讨论CRISPR/CAS9技术的当前和潜在应用及其在临床应用中的局限性，以及通过基因编辑在体细胞或人类胚胎的治疗、疾病预防或残疾方面的伦理和法律考虑。CRISPR/CAS9系统已被成功地用于在广泛的物种中引入基因修改，使其成为遗传工程中的一个强大工具。下面的表1总结了这些应用。目前，这项技术被应用于治疗动物的遗传疾病，但正在推进用于临床治疗人类疾病，特别是那些涉及单基因突变的疾病(Cox等人，2015年)。最近开展并报道了证实CRISPR/Cas9技术确实可以修改致病基因来治疗遗传性疾病的实验。例如，三个研究小组证明，功能正常的dystrophin基因(DMD)可以重新引入缺乏dystrophin的MDX小鼠。这导致了肌肉功能的改善，从肌纤维和心肌细胞，到肌肉干细胞，甚至活体动物(Bararou和Doudna，2016)。此外，其他几个报告证明了CRISPR治疗的体内应用。例如，通过CRISPR/Cas9进行的定向基因组编辑使野生型Fah基因能够在成年小鼠肝脏中表达，并使挽救的肝细胞存活和扩张。蛋白转换酶/枯草杆菌蛋白/kexin 9(PCSK9)的中断也会导致小鼠肝细胞胆固醇代谢的后续变化。综上所述，这些研究证明了利用CRISPR来纠正由单基因突变引起的人类疾病的治疗潜力。CRISPR/CAS9技术在治疗或预防疾病方面的另一个应用包括修饰体细胞。最近批准的一项临床试验证明了这一点，在该试验中，癌症患者的免疫系统细胞被基因编辑为癌症治疗的一种形式。目前，已有多项人体临床试验使用CRISPR治疗肺癌、前列腺癌和肾癌。基因组编辑目前的另一个重要用途是在治疗原发艾滋病毒感染方面，包括通过体外修饰消除CCR5共受体。在CRISPR/Cas9系统开发之前，锌指核酸酶技术被用来干扰艾滋病毒患者的CCR5共受体。这种方法被认为是一种很有前途的基因治疗方法，并进行了临床试验的评估(Tebas等人，2014年)。最近，我们和另外两个研究小组已经证明了CRISPR/Cas9介导的基因组工程可以产生精确的遗传修饰，或者与同源重组一起使用来纠正
The recently developed RNA-guided clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) nuclease system has progressed to be an invaluable technology for genome manipulation in somatic cell types and germline model organisms. While the unprecedented advance in human embryo gene editing research has great potential in next-generation therapeutics, it raises various ethical concerns that need to be addressed before being translated for clinical use. Here, we discuss the current and potential applications of CRISPR/Cas9 technology and its limitations in clinical applications, as well as ethical and legal considerations in the treatment, disease prevention or disability in somatic cells or human embryo via gene editing. The CRISPR/Cas9 system has been successfully utilised to introduce genetic modifications in a wide range of species, rendering it a powerful tool in genetic engineering. These applications are summarised in Table 1 below. Currently, this technology is applied in the treatment of genetic disorders in animals, but is advancing to be clinically used for the treatment of human diseases as well, specifically for those involving single gene mutations (Cox et al., 2015). Experiments to confirm that CRISPR/Cas9 technology can indeed modify pathogenic genes to treat inherited diseases have recently been carried out and reported. For example, three research groups demonstrated that the normally functioning dystrophin gene (Dmd) could be reintroduced in dystrophin-deficient mdx mice. This results in the improvement of muscle function extending from myofibers and cardiocytes, to muscle stem cells and even live animals (Barrangou and Doudna, 2016).Additionally, several other reports have proven the in vivo application of CRISPR treatments. For example targeted genome editing via CRISPR/Cas9 enabled the expression of the wild-type Fah gene and the survival and expansion of rescued hepatocytes in adult mouse liver. Disruptions in protein convertase/subtilisin/kexin type 9 (PCSK9) also result in subsequent changes in cholesterol metabolism seen in mouse hepatocytes. Taken together, these studies demonstrated the therapeutic potential of utilising CRISPR to correct human diseases, which arise from single-gene mutations. Another application of CRISPR/Cas9 technology for the treatment or prevention of diseases includes the modification of somatic cells. This has been demonstrated in a recentlyapproved clinical trial whereby the cells of immune system of cancer patients were genetically edited as a form of cancer therapy. At present, there are a number of human clinical trials using CRISPR against lung, prostate, and renal cell cancers. Another important current use of genome editing is in the treatment of primary HIV infection, involving the elimination of the CCR5 co-receptor via ex vivo modification. Prior to the development of the CRISPR/Cas9 system, zincfinger nuclease technology was utilised to disrupt the CCR5 co-receptor in HIV patients. This method was deemed as a promising approach for gene therapy and proceeded to evaluation for use in clinical trials (Tebas et al., 2014). Recently, we and two other research groups have demonstrated that CRISPR/Cas9 mediated genome engineering can generate precise genetic modification or be used alongside homologous recombination to correct the
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影响因子：
46.9
作者：
Bikard, David;Euler, Chad W.;Jiang, Wenyan;Nussenzweig, Philip M.;Goldberg, Gregory W.;Duportet, Xavier;Fischetti, Vincent A.;Marraffini, Luciano A.
通讯作者：
Marraffini, Luciano A.
DOI：
10.1038/mt.2015.220
发表时间：
2016-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Bakondi B;Lv W;Lu B;Jones MK;Tsai Y;Kim KJ;Levy R;Akhtar AA;Breunig JJ;Svendsen CN;Wang S
通讯作者：
Wang S
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
8.8
作者：
Firth AL;Menon T;Parker GS;Qualls SJ;Lewis BM;Ke E;Dargitz CT;Wright R;Khanna A;Gage FH;Verma IM
通讯作者：
Verma IM
DOI：
10.1126/science.aad5143
发表时间：
2016-01-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nelson CE;Hakim CH;Ousterout DG;Thakore PI;Moreb EA;Castellanos Rivera RM;Madhavan S;Pan X;Ran FA;Yan WX;Asokan A;Zhang F;Duan D;Gersbach CA
通讯作者：
Gersbach CA