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Exciting modification of CRISPR/Cas9 gene editing system leads to disease fighting gene activation

The CRISPR/Cas 9 gene editing technology has undergone ‘second generation’ advancement attempts towards the induction of gene activation, however these efforts have frequently been plagued by technical limitations for in vivo applications [1].  Researchers from the Belmonte lab at the Salk Institute have now successfully added a transcriptional activation domain [1,2,3].  This modification eschews the traditional editing system’s double strand breaks, which are cause for concern as breaks may lead to mutations, which in turn limit their potential use for human disease. The new approach effectively confers epigenetic changes in gene expression, as the DNA sequence remains unaltered – opening a pathway for eventual use in humans. 

The team tested individual packaging combinations of the discrete molecular components used in the conventional editing system, with some modifications, into the adenovirus vehicle required for delivery [1,2,3]. The fusion of CAS9 with the activator previously presented problems, as the resulting protein was too large for delivery into the vehicle. In this new work, the vehicle was separately packaged with either CAS9, or a ‘dead’ version CAS9 lacking nuclease activity, or with the guide RNAs required for genomic targeting along with molecular activation switches; the appropriate combination induced the activation of target genes. In very exciting functional experiments that followed, the group tested their system in mice and observed activation of genes involved in kidney disease, type 1 diabetes and muscular dystrophy. The reported results demonstrated physiological improvements. The team is working to improve this system and to increase the number of diseases they can target with their sights set on ultimately testing for safe use in humans.     




References and Sources

[1]H-K Liao, F Hatanaka, T Araoka, P Reddy, M-Z Wu, Yi Sui, T Yamauchi, M Sakurai, DD O’Keefe, E Núñez-Delicado, P Guillen, JM Campistol, C-J Wu, L-F Lu, CR Esteban, JCI Belmonte. In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans -epigenetic Modulation. Cell, 2017; DOI: 10.1016/j.cell.2017.10.025

[2]Cell Press. (2017, December 7). CRISPR-Cas9 technique targeting epigenetics reverses disease in mice. ScienceDaily. Retrieved December 12, 2017 from www.sciencedaily.com/releases/2017/12/171207141735.htm



Graphical abstract from [1], illustrating target gene activation in mice.

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