Correction of a genetic defect in multipotent germline stem cells using a human artificial chromosome
Correction of a genetic defect in multipotent germline stem cells using a human artificial chromosome
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DOI：
10.1038/sj.gt.3303091
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发表时间：
2008-04-01
期刊：
影响因子：
5.1
通讯作者：
Oshimura, M.
中科院分区：
文献类型：
--
作者：
Kazuki, Y.;Hoshiya, H.;Oshimura, M.
人类人工染色体（HAC）作为基因治疗载体具有几个优点，包括避免插入突变的稳定附加型维持和携带包括调控元件的大基因插入物的能力。多能生殖干细胞（mGS）具有巨大的基因治疗潜力，因为它们可以从个体的睾丸中产生，并且当重新引入时可以有助于任何组织的专门功能。作为概念的证明，我们在此报告了小鼠p53（-/-）mGS细胞中遗传缺陷的功能恢复，使用具有通过微细胞介导的染色体转移引入的基因组人类p53基因的HAC。通过引入p53-HAC补充了基因调控和辐射敏感性的p53表型，并且细胞在体内和体外分化成几种不同的组织类型。因此，使用mGS细胞与HAC的组合为基因和细胞治疗提供了新的工具。下一步是使用动物模型证明功能恢复，用于未来的基因治疗。
Human artificial chromosomes (HACs) have several advantages as gene therapy vectors, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including regulatory elements. Multipotent germline stem (mGS) cells have a great potential for gene therapy because they can be generated from an individual's testes, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we herein report the functional restoration of a genetic deficiency in mouse p53(-/-) mGS cells, using a HAC with a genomic human p53 gene introduced via microcell-mediated chromosome transfer. The p53 phenotypes of gene regulation and radiation sensitivity were complemented by introducing the p53-HAC and the cells differentiated into several different tissue types in vivo and in vitro. Therefore, the combination of using mGS cells with HACs provides a new tool for gene and cell therapies. The next step is to demonstrate functional restoration using animal models for future gene therapy.