This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Some genetic diseases leave cells without a crucial protein. One possible treatment is to persuade genes already inside those cells to work harder, but the necessary machinery can be difficult to deliver, especially when researchers want to target several genes at once.
A new compact CRISPR system devised by Hainan Zhang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and colleagues fits those instructions into a single viral delivery package. In separate mouse experiments, the treatment reduced seizures and prevented early deaths in a model of Dravet syndrome, and it produced lasting improvements in muscle function in a model of Duchenne muscular dystrophy. These results, published in Nature Biotechnology, suggest that turning up helpful genes rather than repairing mutations may be a better way to influence cell behavior in genetic diseases.
The system uses CRISPR activation, which directs molecular machinery to a gene's control region to increase its activity without cutting the DNA. But delivering that machinery creates a packaging problem because adeno-associated viruses, which are used to carry genetic instructions into cells, have limited cargo space. The package must incorporate both the protein that helps activate genes and the RNA guides that direct it to the right places.
The researchers built their system around Cas12m, a small CRISPR protein that can also cut a chain of RNA guides into separate working pieces inside a cell. In this way, several guides can share one compact set of instructions. After engineering the protein and its accompanying components, the team created a platform called smCRISPRa that allows multiple guides to focus its activity on one gene or distribute it across several.
In one demonstration, a single viral vector carried eight guides that increased the activity of six genes in mouse brain and muscle tissues. In the Dravet syndrome model, the mice had only one functional copy of Scn1a, leaving them without a protein needed for normal brain signaling. The researchers injected the viral delivery package into fluid-filled spaces in the brains of newborn mice.
The treatment raised protein levels to normal or higher and reduced seizures. All 31 treated mice survived the roughly 100-day observation period, compared with about 60% of 30 disease-model mice that were given a control injection. To treat Duchenne muscular dystrophy, the team pursued a different solution.
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