CRISPR-based framework smothers qualities identified with AAV antibody production

CRISPR-based framework smothers qualities identified with AAV antibody production


  • Post By : Kumar Jeetendra

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  • Date: 09 Sep,2020

Gene therapy generally is based on viruses, such as adeno-associated virus (AAV), to deliver genes into a cell. In the event of CRISPR-based gene therapies, molecular scissors can then snip out a faulty gene, add in a missing arrangement or enact a temporary change in its expression, but the body’s immune response to AAV can thwart the whole endeavor.

To overcome that barrier, researchers at the University of Pittsburgh School of Medicine created a system that uses CRISPR in another way. Their system temporarily suppresses genes that are related to AAV antibody production so the virus can deliver its cargo unimpeded. These results published today in Nature Cell Biology.

So Kiani and her long-time collaborator Mo Ebrahimkhani, M.D., associate professor of pathology at Pitt, member of PLRC and MIRM, set out to modify gene expression about the body’s immune response to AAV. However, this gene is essential for normal immune function, so the researchers didn’t want to shut it down forever, just tamp it down .

Many clinical trials fail because of the immune response against AAV gene therapy. And then you can’t readminister the shot because people have developed immunity.”-Samira Kiani, MD, Study Co-Senior Author and Associate Professor of Pathology, Member of the Pittsburgh Liver Research Center (PLRC) and McGowan Institute for Regenerative Medicine (MIRM), University of Pittsburgh

Since CRISPR is this a convenient system for editing the genome, the group figured they would put it to use for altering the master switches which orchestrate genes involved in immune response.

“You can use CRISPR to do your gene therapy, and you also can use CRISPR to control the immune response.”

These animals were more receptive to subsequent AAV-delivered gene treatment when compared with controls.

Beyond gene therapy, the study also shows that CRISPR-based immune suppression can prevent or treat sepsis in mice, highlighting the potential for this tool to be widely useful for a selection of inflammatory conditions, including cytokine storm and acute respiratory distress syndrome, both of which may crop up with COVID-19, though more studies are needed to engineer security features.

“The main objective of the study was to create CRISPR-based tools for inflammatory conditions,” said study lead author Farzaneh Moghadam, a Ph.D. student in Kiani’s lab.

“However, when we looked at bone marrow samples, we saw that the group treated with our tool showed a lower immune response to AAV in comparison to the control group. That was really interesting, so we started exploring this instrument contributes to antibody formation against AAV and could potentially address safety and efficacy issues with gene therapy trials.”

Kiani cofounded SafeGen Therapeutics with the objective of bringing this technology into the clinic.

Journal reference:

Moghadam, F., et al. (2020) Synthetic immunomodulation with a CRISPR super-repressor in vivo. Nature Cell

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