After years of disappointment, gene-therapy research has undergone a renaissance, with several high-profile drug approvals and a string of promising clinical-trial results against devastating genetic diseases, including sickle-cell disease and some blood cancers.
But as researchers attempt to develop treatments for new conditions, they are also trying to work out how to cope with worrying signs that immune responses to the therapies could hinder their efforts — and generate dangerous side effects.
Immune interference
Researchers have long been wary of how immune responses could make gene therapies less effective. The treatments often rely on a virus to ferry a gene into cells, but if the recipient already has antibodies against that virus, an immune response could hinder the treatment. As a result, participation in gene-therapy clinical trials is often limited to people who do not already have such antibodies.
Inflammatory response
The main concern used to be that antibodies against an AAV or its cargo would prevent the gene therapy from working or preclude the possibility of giving multiple doses, said Wright. But more recently, researchers have realized that antibodies could stimulate the production of inflammatory molecules, activate cell-death pathways and trigger the development of killer T cells that could target AAV-containing cells for destruction.
Researchers at the ASGCT meeting reported efforts to tackle this inflammation from a variety of angles. Some are looking for alternatives to AAVs, and Collins noted that the NIH’s Somatic Cell Genome Editing programme is studying both viral and non-viral vectors.
Suppressed immunity
Others are working on ways to suppress harmful immune responses. Gene therapies are often given with immunosuppressants such as steroids, but there are concerns that such treatments are sometimes ineffective, and can render recipients vulnerable to infection. Anastasia Conti, who studies stem cells at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, reported at the ASGCT meeting that a drug called anakinra reduced inflammation triggered by gene editing. The drug might also enhance the potency of gene-editing treatment by reducing the number of edited blood stem cells that become senescent — meaning that they are still alive but have stopped dividing.
How the immune system could stymie some CRISPR gene therapies?
At Selecta Biosciences in Watertown, Massachusetts, researchers are developing nanoparticles designed to be taken up by immune cells and coupled to a drug called rapamycin that is sometimes used to suppress the immune system after organ transplantation. In non-human primates, the team found that three monthly doses of the nanoparticles prevented antibody responses to the AAV’s protein shell, chief scientific officer Kei Kishimoto said at the meeting. And researchers at Spark have tested a drug that inhibits an immune regulator called IL-6. They found that the treatment lowered the level of antibodies against AAV shells in non-human primates. In mice, it reduced immune responses enough to allow the animals to receive multiple rounds of gene therapy.
In the end, it will probably take a “toolbox of strategies” to tackle the inflammation problem, said Chan. And as the reach of gene therapies continues to expand, researchers need to develop tools to monitor potentially dangerous inflammation in difficult-to-access parts of the body, such as the brain, he added.