Skoltech, MIT, UMass researchers develop gene-editing solution to liver diseases


Researchers from Skoltech, the Massachusetts Institute of Technology (MIT) and the University of Massachusetts (UMass) have developed novel nanoparticles that can deliver the CRISPR-Cas9 genome editing system and specifically modify genes directly within the liver of a mouse. Researchers were able to remove target genes in approximately 80% of hepatocytes – the best rate ever achieved with CRISPR in adult animals.

CRISPR-Cas9 is a gene editing technology that makes it possible to modify genes within a living being. Researchers in laboratories around the globe are hard at work attempting to develop safe and efficient delivery methods for the CRISPR gene-editing system, which consists of DNA-cutting enzyme Cas9 and a short sgRNA that guides Cas9 to a specific region in the genome.

A joint study, published this week in Nature Biotechnology, describes a new system developed by researchers from Skoltech, MIT and UMass that delivers both Cas9 mRNA and sgRNA using lipid nanoparticles, without any viral components. The most common approach is based on viruses carrying the Cas9 gene and the sgRNA. Viral delivery is a promising approach but it cannot be applied in certain situations, with immunogenicity posing the main problem in this respect. Additionally, the high-pressure injection needed for the delivery potentially can lead to liver damage. The team used lipid nanoparticles to deliver the CRISPR components while avoiding the drawbacks of viral vectors. Another key achievement of the study was the emergence of certain sgRNA chemical modifications resulting in prominent stability and efficacy enhancement in comparison with the native sgRNA.

The researchers focused on the Pcsk9 gene as a target that regulates cholesterol metabolism. The US Food and Drug Administration (FDA) has recently approved two antibodies targeting Pcsk9, that patients must use twice monthly for the whole of their lifetimes. The CRISPR system described by the authors permanently edits the Pcsk9 gene after a single treatment. The researchers were able to eliminate this gene in more than 80% of hepatocytes, lowering the levels of Pcsk9 protein to undetectable in serum. This resulted in a 35% reduction of circulating cholesterol in the treated mice. The technique will be further developed to treat other liver disorders, with probable advancement towards use in patients.

The research was supported by the National Institutes of Health (NIH), Skoltech, the Russian Scientific Foundation and a Cancer Center Support grant from the NIH.


Feature image: Christoph Bock, Max Planck Institute for Informatics // Wikimedia Commons.

Tweet about this on Twitter0Share on Facebook0Pin on Pinterest0Share on Tumblr0Share on VK