New CRISPR/Cas9 delivery method could offer a clinical pathway

UMass' Wen Xue

CRISPR/Cas9 gene editing is a rapidly developing technique that is thought to provide revolutionary new ways to manipulate genes for the treatment of a number of diseases. Delivering the CRISPR therapeutic in an efficient, safe and predictable way, though, has been difficult--to this end, researchers at UMass have created a means of administering the gene editor that could help send it to clinical trials.

CRISPR/Cas9 is a natural immune system in bacteria used to protect them from foreign genetic material, and scientists have used its components to cut and repair DNA sequences to replace faulty, disease-causing portions with corrected versions.

The difficulty comes about in getting the separate components (the Cas9 "scalpel," the DNA repair template and an RNA guide) to the genetic material in a target cell. Previous attempts at delivering the system through disruptive, high-powered injection has caused damage to the liver and required too much volume when treating mice with metabolic diseases.

The new delivery method involves a two-part process. The researchers loaded (in a mouse model) both the CRISPR guide RNA and the DNA template into a viral vector without the Cas9 "scalpel" sequence. Because that crucial aspect was missing in this first injection, the genetic editing material remained inactive. This gives the patient some time to produce new RNA guide strands and DNA templates before the Cas9 is introduced.

A week after the first injection, the scientists deliver the Cas9 messenger RNA wrapped in lipid nanoparticles. In mice with the metabolic disease Tyrosinemia type I, the gene editing led to a reduction in weight loss, lower liver damage and the generation of liver cells with the corrected gene. The work was published in Nature Biotechnology.

"This is the first study to provide proof that the CRISPR/Cas9 gene editing system can be administered in a therapeutically applicable formulation to repair genes in live, adult animals," UMass researcher and study co-author Wen Xue said in a statement. "Until now it's not been possible to deliver CRISPR/Cas9 in a way that was suitable for clinical trials. By using an RNA guide and DNA repair template delivered via viral vector followed by a Cas9 in a lipid nanoparticle, we've take a huge step forward to overcoming this hurdle."

- here's the UMass report
- get the journal abstract

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