Optogenetic CRISPR gene-editing demonstrates potential for controlling genome modifications in medical therapeutics

Research, led by scientists at the University of Tokyo, has demonstrated the development of a photo-activatable Cas9 nuclease, capable of regulating CRISPR gene-editing activity through exposure to blue light. The research, published in the journal Nature Biotechnology (doi:10.1038/nbt.3245, 2015), reported the creation of a photo-activatable Cas9 by splitting the normal Cas9 protein into two inactive fragments and then attaching a light activatable domain to each fragment.  When the fragments are exposed to blue light they come together re-forming functional Cas9 activity. The process is reported to be reversible – when the light is turned off, the Cas9 nuclease splits back into its fragments and CRISPR activity is turned off.  CRISPR gene editing tools have significant potential for therapeutic treatment of a broad range of genetic diseases, including several ophthalmic disorders.


The relatively recent introduction of CRISPR – “clustered regularly interspaced short palindromic repeats” – a novel gene-editing technology, has generated significant interest in the biomedical community, not least of all due to its low cost, its incredible ease of use and its versatility across a broad range of applications. Mediated by the Cas9 nuclease and short guide RNAs, the technology has emerged from research into prokaryotic immune defence systems dating back to the late 1980s. However, research reported in a 2012 paper published in Science by Martin Jinek and colleagues at the University of California, Berkeley, in collaboration with the University of Vienna and Umeå University in Sweden, showed that the technology could be harnessed into an “efficient, versatile, and programmable” editing tool with “considerable potential for gene-targeting and genome-editing applications.” Further iterations and development showed how relatively easy the CRISPR/Cas9 system could be used as an RNA-guided platform for specific control of gene expression. Recently, the CRISPR system has been shown to correct congenital cataract in mammalian models, with many additional applications in the pipeline. The core technologies have been developed by a number of key players, chiefly the founding scientists currently associated with several start-up companies including Crispr Therapeutics (Basel, Switzerland), Editas Medicine (Cambridge, Massachusetts), Caribou Biosciences, Inc. (Berkeley, California), Intellia Therapeutics (Cambridge, Massachusetts), and ERS Genomics (Dublin, Ireland).


The recent Japanese research employed an engineered photo-activatable Cas9 to enable optogenetic control of CRISPR-Cas9 genome editing in human embryonic kidney 293T cells. The authors of the study claim that, “optogenetic control of targeted genome editing should facilitate improved understanding of complex gene networks and could prove useful in biomedical applications”. The development of CRISPR gene editing has already under-gone proof-of-concept studies in models of congenital cataract however, light controllable activation of the targeted nuclease activity may be particular applicable to treating ocular disorders. The Japanese researchers are already understood to be developing variations activatable by different wavelengths of lights.