Suppose you have developed the winning weapon to defeat certain genetic diseases by reliably correcting pathogenic mutations. There is still a problem: how do you march onto the battlefield, inside sick cells? The weapon is the genome-editing machinery, and the most efficient vessel ever tested are lipid nanoparticles. With this approach, described in a study published in Nature Biotechnology last week, CRISPR has beaten its success record in adult animals, knocking out the target gene in about 80% of liver cells.

Hao Yin, Daniel Anderson, and their colleagues at the Massachusetts Institute of Technology were looking for an alternative to traditional viral vectors used in gene therapy because in certain situations viruses are less than ideal. They experimented their new method based on nanoparticles in mice, silencing a gene that regulates cholesterol levels (Pcsk9) and is responsible for a rare disease called dominant familial hypercholesterolemia. This gene can also be inhibited more conventionally, but patients must take drugs regularly for the rest of their life. A genetic intervention, in contrast, could solve the problem once and for all.

The CRISPR system has two main components: a DNA-cutting protein called Cas9 and its RNA guide. The MIT team, therefore, decided to inject nanoparticles containing the messenger RNA encoding for Cas9 and also nanoparticles carrying the RNA guide, suitably modified to protect it from enzymes in the body. The target gene was successfully knocked out as a result, and cholesterol levels fell by 35% in the treated animals. The next step will be to try and do the same with other liver disorders.

Last month a study published in Nature Biomedical Engineering described how to fix a pathogenic mutation in a mouse model of Duchenne muscular dystrophy with the help of another non-viral delivery system: gold nanoparticles. Researchers made the CRISPR components adhere to tiny balls of the precious metal, bonding them to each other. The resulting complex, renamed CRISPR-Gold, was injected locally. The mutation was repaired in about 5% of the copies of the gene in injected muscles, improving muscle function in mice. A good result, considering that the correction rate was less than 1% without the nanoparticles. (Photo credit: MIT News)