How CRISPR is tackling the troubling immune response that’s plagued gene therapy until now
Gene therapy: Past and present
Traditionally scientists use viruses — from which dangerous disease-causing genes have been removed — as vehicles to transport new genes to specific organs. These genes then produce a product that can compensate for the faulty genes that are inherited genetically. This is how gene therapy works.
Though therehave been examplesshowing thatgene therapy was helpfulin some genetic diseases, they are still not perfect. Sometimes, a faulty gene is so big that you can’t simply fit the healthy replacement in the viruses commonly used in gene therapy.
Another problem is that when the immune system sees a virus, it assumes that it is a disease-causing pathogen and launches an attack to fight it off by producing antibodies and immune response – just as happens when people catch any other infectious viruses, like SARS-CoV-2 or the common cold.
Recently, though, with the rise of agene-editing technology called CRISPR, scientists can do gene therapy differently.
CRISPR can be used in many ways. In its primary role, it acts as a genetic surgeon with a sharp scalpel, enabling scientists to find a genetic defect and correct it within the native genome in desired cells of the organism. It can also repair more than one gene at a time.
Scientists can also use CRISPR to turn off a gene for a short period of time and then turn it back on, or vice versa, without permanently changing the letters of DNA that makes up our genome. This means that researchers like me can leverage CRISPR technology to revolutionize gene therapies in the coming decades.
But to use CRISPR for either of these functions, it still needs to be packaged into a virus to get it into the body. So some challenges, such as preventing the immune response to the gene therapy viruses, still need to be solved for CRISPR-based gene therapies.
Being trained asa synthetic biologist, I teamed up with Ebrahimkhani to use CRISPR to test whether we could shut down a gene that is responsible for the immune response that destroys the gene therapy viruses. Then we investigated whether lowering the activity of the gene, and dulling the immune response, would allow the gene therapy viruses to be more effective.
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Preventing the immune response that destroys gene therapy viruses
A gene called Myd88is a key gene in the immune system and controls the response to bacteria and viruses, including the common gene therapy viruses. We decided to temporarily turn off this gene in the whole body of lab animals.
We injected animals with a collection of the CRISPR molecules that targeted the Myd88 gene and looked to see whether this reduced the number of antibodies that were produced to specifically fight our gene therapy viruses. We were excited to see that the animals that received our treatment using CRISPR produced less antibodies against the virus.
This prompted us to ask what happens if we give the animal a second dose of the gene therapy virus. Usually, the immune response against a gene therapy virus prevents the therapy from being administered multiple times. That’s because after the first dose, the immune system has seen the virus, and on the second dose, antibodies swiftly attack and destroy the virus before it can deliver its cargo.
We saw that animals receiving more than one dose did not show an increase in antibodies against the virus. And, in some cases, the effect of gene therapy improved compared with the animals in which we had not paused the Myd88 gene.
We also did a number of other experiments that proved that tweaking the Myd88 gene can be useful in fighting off other sources of inflammation. That could be useful in diseases like sepsis and even COVID-19.
While we are now beginning to improve this strategy in terms of controlling the activity of the Myd88 gene. Our results, now published inNature Cell Biology, provide a path forward to program our immune system during gene therapies and other inflammatory responses using the CRISPR technology.
This article is republished fromThe ConversationbySamira Kiani, Associate Professor of Pathology,University of Pittsburghunder a Creative Commons license. Read theoriginal article.
Story byThe Conversation
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