Return of gene therapy: How to make the treatment safer

At the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, viral immunologist Ying Kai Chan is trying to develop safer AAV vectors. The risks increased when researchers used larger amounts of AAV, he told the conference: “I’m a big fan of reducing the dose.” But this may require the development of more effective treatments that use fewer viruses, he added he added.

“I’m a big fan of reducing the dose”(Ying Kai Chan, Immunologe)

Some scientists are trying to “humanize” the AAV genome to make it less likely to trigger certain immune responses in the body. For example, when DNA base C is followed directly by base G in the genome sequence, in humans it often bears a chemical group called methyl. AAV has a higher percentage of non-methyl CG groups – a potential warning sign for the immune system. Wright presented data showing that increasing methylation of CG-rich regions decreases activation of pro-inflammatory molecules called cytokines. However, he also mentioned the potential downside: the same methylation, if too present, could also repress gene expression, including that of the therapeutic gene carried by the AAV.

Curb the immune system

Other research groups are working on ways to suppress harmful immune responses. Gene therapies are already often administered together with immunosuppressants such as steroids. However, there are concerns that it may render treatments ineffective and make recipients more susceptible to infection. Anastasia Conti, who researches stem cells at the San Raffaele Telethon Institute for Gene Therapy in Milan, reported at the ASGCT meeting that the drug anakinra reduces the inflammation caused by the gene changes. Anakinra could also increase the effectiveness of genome-editing treatment by reducing the number of altered blood stem cells that have already stopped dividing.

At Selecta Biosciences in Watertown, Massachusetts, researchers are developing nanoparticles that can be loaded with rapamycin and taken up by immune cells. This drug is sometimes used to suppress the immune system after organ transplants. Chief Scientific Officer Kei Kishimoto told the meeting that his team found in primates that three monthly doses of the packed nanoparticles prevented antibody responses to the AAV protein envelope. Spark researchers have also tested a drug that inhibits the immune regulator IL-6. They were able to show that the treatment in primates reduces the amount of antibodies against AAV envelopes. In mice, the drug reduced the immune responses to such an extent that the animals could receive multiple rounds of gene therapy.

“Ultimately, a whole bundle of strategies will probably be needed to get the inflammatory problem under control,” said immunologist Ying Kai Chan. And as gene therapies continue to grow, researchers will need to develop tools to monitor potentially dangerous inflammation in hard-to-reach parts of the body, such as the brain, he added. Many studies of inflammation have been done in the eye, where researchers can visualize changes that occur months after therapy with relative ease. But, “How can we really know what’s happening in the central nervous system or in the ear?” Chan asked. His concern is that one could delude oneself for a long time.