The ability to edit the human genome using CRISPR has been heralded as a revolution in medicine. However, one of the biggest challenges facing gene therapies is getting this molecule gene-editing machinery into cells. Among the most common delivery approaches is the use of viruses such as the adeno-associated virus (AAV), which shuttle CRISPR into the nuclei of cells where these molecular scissors can then make edits to the defective gene.
The immune system shields us from invading pathogens and CRISPR-bearing AAVs are no exception. Consequently, patients can launch strong immune responses against gene therapies, rendering them useless.
In designing a means of side-stepping these immune reactions, scientists at the University of Pittsburgh are once again turning to CRISPR. A newly developed system temporarily hits pause on genes associated with the production of antibodies against AAV. This suspension of the immune system provides AAV with a safe passage into cells where they can drop off their CRISPR cargoes without immune intervention.
“Many clinical trials fail because of the immune response against AAV gene therapy,” said Samira Kiani, senior author of the study which was published in Nature Cell Biology. “And then you can’t readminister the shot because people have developed immunity.”
The scientists validated their system of controlling the immune system with CRISPR in an experimental mouse model. They first administered AAVs bearing CRISPR sequences that pumped the brakes on the immune system. The second infusion of AAV contained CRISPR targeting another gene to simulate gene therapy. Promisingly, the mice did not mount an immune response against the second shot of AAV, with the therapy working much more efficiently than in control animals.
Kiani has gone on to launch SafeGen Therapeutics, a start-up aimed at bringing this technology to the clinic.