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Biography

My laboratory’s expertise is in genome editing and gene therapies. I have received my Ph.D. degree in 2007 and postdoctoral training during 2012 to 2014. I have gained China Youth Thousand Talents Program in 2014 and Outstanding Youth Science Foundation in 2015. I began my research career as a pioneer making genetically modified mice including semi-cloned mice by androgenetic haploid stem cells and CRISPR-editing mice, some of which have produced important advances in understanding genetic diseases, and developmental abnormalities.Recently,the lab has demonstrated thatfully functional knockout monkey in F0 and knock-in monkey could be generated by optimized CRISPR/Cas9 system. We have also demonstrated the use of the CRISPR/Cas9 system to eliminate targeted chromosomes via multiple DNA cleavages, offering a new therapeutic strategy for human aneuploidy diseases involving additional chromosomes.My group is interested in establishing a powerful platform to generate genetically humanized animals, including rodent and non-human primate, and develop an efficient genetic approach to correct genetic diseases in these humanized animal models.

Abstract

CRISPR application in animals and gene therapies

Hui Yang

Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China

The CRISPR/Cas9 technology provides a promising tool for genetic engineering. It offers an efficient approach to develop genetically modified (GM) animal models and a potential strategy for targeted gene therapies. We previously applied the CRISPR/Cas9 system to generate knockout mice and knock-in mice, although with mosaicism and relatively low efficiency. Recently, we optimized CRISPR/Cas9 system and obtained fully functional knockout mice and monkey in F0, which could be directly used for phenotypical analysis. We also devised a homology-mediated end joining (HMEJ)-based strategy, yielding knock-in mice and monkeys, with an efficiency much higher than other knock-in strategies. For targeted gene therapies, we rescued Fah^−/− liver failure mice by correcting Fah mutation using microhomology-mediated end joining (MMEJ) and HMEJ-based strategies. Furthermore, we demonstrate the use of the CRISPR/Cas9 system to eliminate targeted chromosomes via multiple DNA cleavages, offering a new therapeutic strategy for human aneuploidy diseases involving additional chromosomes. Finally, we achieved multiple genes activation in vivo using CRISPR–dCas9- activator, leading to observable phenotypic changes in liver and brain. This offers a new approach for developing targeted epigenetic therapies against human diseases. In this oral presentation, I will describe a targeting strategy, termed Tild-CRISPR. Compared with existing targeting strategies, this method achieved much higher knock-in efficiency in mouse embryos, as well as mouse brain using in utero electroporation. Importantly, this Tild-CRISPR method yielded higher knock-in efficiencies (up to 12 fold) than homology recombination (HR)-based method in human embryos, suitable for studying gene functions in vivo and developing potential gene therapies.

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