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Mol Ther Nucleic Acids. 2016;5:e349. doi: 10.1038/mtna.2016.58.

CRISPR-Cas9 for in vivo Gene Therapy: Promise and Hurdles.

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Department of Pediatrics, Jiangsu Huai'an Maternity and Children Hospital, Huai'an, China.
Department of Hepatology, the Fourth People's Hospital of Huai'an, Huai'an, China.
Department of Stomatology, The First People's Hospital of Lianyungang, Jiangsu, China.
Department of Nephrology, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China. Electronic address:
Department of Clinical Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China. Electronic address:
Department of Gastroenterology, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.


Owing to its easy-to-use and multiplexing nature, the genome editing tool CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9) is revolutionizing many areas of medical research and one of the most amazing areas is its gene therapy potentials. Previous explorations into the therapeutic potentials of CRISPR-Cas9 were mainly conducted in vitro or in animal germlines, the translatability of which, however, is either limited (to tissues with adult stem cells amenable to culture and manipulation) or currently impermissible (due to ethic concerns). Recently, important progresses have been made on this regard. Several studies have demonstrated the ability of CRISPR-Cas9 for in vivo gene therapy in adult rodent models of human genetic diseases delivered by methods that are potentially translatable to human use. Although these recent advances represent a significant step forward to the eventual application of CRISPR-Cas9 to the clinic, there are still many hurdles to overcome, such as the off-target effects of CRISPR-Cas9, efficacy of homology-directed repair, fitness of edited cells, immunogenicity of therapeutic CRISPR-Cas9 components, as well as efficiency, specificity, and translatability of in vivo delivery methods. In this article, we introduce the mechanisms and merits of CRISPR-Cas9 in genome editing, briefly retrospect the applications of CRISPR-Cas9 in gene therapy explorations and highlight recent advances, later we discuss in detail the challenges lying ahead in the way of its translatability, propose possible solutions, and future research directions.

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