One of the major challenges facing gene therapy — a way to treat disease by replacing a patient’s defective genes with healthy ones — is that it is difficult to safely deliver therapeutic genes to patients without the immune system destroying the gene, and the vehicle carrying it, which can trigger life-threatening widespread inflammation.
Three decades ago researchers thought that gene therapy would be the ultimate treatment for genetically inherited diseases like hemophilia, sickle cell anemia, and genetic diseases of metabolism. But the technology couldn’t dodge the immune response.
Since then, researchers have been looking for ways to perfect the technology and control immune responses to the gene or the vehicle. However, many of the strategies tested so far have not been completely successful in overcoming this hurdle.
Drugs that suppress the whole immune system, such as steroids, have been used to dampen the immune response when administering gene therapy. But it’s difficult to control when and where steroids work in the body, and they create unwanted side effects. My colleague Mo Ebrahimkhani and I wanted to tackle gene therapy with immune-suppressing tools that were easier to control.
I am a medical doctor and synthetic biologist interested in gene therapy because six years ago my father was diagnosed with pancreatic cancer. Pancreatic cancer is one of the deadliest forms of cancer, and the currently available therapeutics usually fail to save patients. As a result, novel treatments such as gene therapy might be the only hope.
Yet, many gene therapies fail because patients either already have pre-existing immunity to the vehicle used to introduce the gene or develop one in the course of therapy. This problem has plagued the field for decades, preventing the widespread application of the technology.
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 there have been examples showing that gene therapy was helpful in 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 a gene-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 as a 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.