Nat Cell Biol: Editing the immune response using CRISPR makes gene therapy more effective.

September 17, 2020 /--- gene therapy generally relies on viruses such as adeno-related viruses (AAVs) to deliver genes to cells.
In CRISPR-based gene therapy, molecular scissors can remove defective genes and add a missing sequence or temporarily alter its expression, but the body's immune response to AAV can hamper the entire effort.
to overcome this obstacle, researchers from the University of Pittsburgh School of Medicine in the United States built a system that uses CRISPR in different ways in a new study.
their systems briefly inhibited genes associated with AAV antibody production so that the virus could deliver the genetic cargo it carried without obstruction.
study was recently published in the journal Nature Cell Biology under the title "Synthetic immunomodulation with a CRISPR super-repressor in vivo".
photo from Nature Cell Biology, 2020, doi:10.1038/s41556-020-0563-3.
clinical trials fail because of the immune response to AAV gene therapy," said Dr. Samira Kiani, co-author of the paper and an associate professor of pathology at the University of Pittsburgh.
you can't re-inject the virus vector because people are already immune to it, " he said.
", Kiani and her longtime collaborator, Dr. Mo Ebrahimkhani, began to modify gene expression associated with the body's immune response to AAV.
, such a gene is important for normal immune function, and the researchers don't want to turn it off forever, they just want to suppress it for the time being.
given that CRISPR is such a convenient system for editing genomes, Kiani and Ebrahimkhani think they will use it to change the main switch that coordinates genes involved in the immune response.
, "We can do one stone and two birds," said Ebrahimkhani, a spokesman for the Group.
you can use CRISPR for gene therapy, you can also use CRISPR to control the immune response.
the researchers treated mice with their CRISPR-controlled immunosuppressive system and then exposed them again to AAV, they did not produce more antibodies to fight the virus.
were more likely to receive follow-up AAV-based gene therapy than control mice.
In addition to gene therapy, the study also showed that CRISPR-based immunosuppression can prevent or treat sepsis in mice, highlighting the tool's potential for widespread usefulness in treating a range of inflammatory diseases, including cytokine storms and acute respiratory distress syndrome, both of which occur in patients with COVID-19, although more research is needed to design safe functions.
the main goal of this study is to develop CRISPR-based tools to treat inflammatory diseases," said Farzaneh Moghadam, ph.D. student at Kiani Labs and lead author of the paper.
but when we looked at bone marrow samples, we found that mice treated with our tools had a lower immune response to AAV than control mice.
it's very interesting, so we're starting to explore how this tool can help reduce antibody formation against AAV and potentially address the safety and effectiveity of gene therapy trials.
" Kiani co-founded SafeGen Therapeutics with the goal of applying this technology to the clinic.
(bioon.com) Reference: 1.Farzaneh Moghadam et al. Synthetic immunomodulation with a CRISPR super-repressor in vivo. Nature Cell Biology, 2020, doi:10.1038/s41556-020-0563-3.2.Editing immune response can make gene the morerapy effective.