A team from the Salk Institute has developed a new version of the CRISPR-Cas9 genome editing technology allowing them to selectively activate genes in mice without breaking the DNA. The team has therefore succeeded in improving the condition of mice suffering from type 1 diabetes, acute renal failure and muscular dystrophy.
"Although many studies have shown that CRISPR Cas9 can be used as a powerful genetic tool, there are major concerns about the unwanted mutations generated with this technology. We have been able to overcome this problem," confirmed Juan Carlos Izpisua Belmonte, main author of the study published in the Cell journal on 7 December. To achieve this, they used a specific form of the Cas9 enzyme, which targets specific places in the genome without cutting the DNA. Coupled with areas of transcriptional activation, such as "molecular commutators", the system can precisely activate a gene. The technique therefore functions epigenetically. It affects gene activity without modifying the DNA sequence. However, this new tool is bulky and difficult to transport in living organisms. This complicates its use in clinical applications. To overcome this obstacle, the team separated the various tool components, facilitating their transport whilst guiding each component to ensure that it reaches the desired location.
For their experiments in mice, they designed a CRISPR-Cas9 system for each disease, targeting one or more genes that could potentially reverse the symptoms. They thus improved renal function by activating two genes, lowered blood glucose levels in diabetic mice thanks to gene activation and modified an inaccessible gene using conventional gene therapy in mice presenting with muscular dystrophy.
The team welcomes these results: "By triggering the activation of certain genes, physiological changes were noted at the same time," they concluded. To date they have been working on improving system specificity to apply it to various types of cells and organs, and to treat a wide range of diseases. A considerable amount of research is still required.
 Cell, Liao et al.: "In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-Epigenetic Modulation"
AFP (8/12/2017); Phys.org (7/12/2017)