Return of gene therapy: how to make treatment safer

At Harvard University’s Wyss Institute for Biologically Inspired Engineering in Boston, Massachusetts, viral immunologist Ying Kai Chan is trying to develop safer AAV vectors. Risks increased as researchers used larger amounts of AAV, she told the conference, “I’m a huge fan of dose reduction.” However, this may require developing more effective treatments that use fewer viruses, she added.

“I’m a huge fan of dose reduction.”(Ying Kai Chan, Immunology)

Scientists are trying to “humanize” the AAV genome to make it less likely to activate certain immune responses in the body. For example, when the DNA base C is followed directly by the base G in the genome sequence, in humans it often carries 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 increased methylation of CG-rich regions decreases the activation of pro-inflammatory molecules called cytokines. However, he also mentioned the potential downside: methylation itself, if too present, could also repress gene expression, including that of the therapeutic gene carried by the AAV.

Restrain the immune system

Other research groups are working on ways to suppress harmful immune responses. Gene therapies are already often given alongside immunosuppressants such as steroids. However, there is concern that it may render treatments ineffective and make recipients more susceptible to infections. Anastasia Conti, who researches stem cells at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, told the ASGCT meeting that a drug called anakinra reduces inflammation caused by gene changes. The drug 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 a drug called rapamycin and taken up by immune cells. Rapamycin is sometimes used to suppress the immune system after organ transplants. In primates, his team found that three monthly doses of the packaged nanoparticles prevented antibody responses to the AAV protein envelope, lead scientist Kei Kishimoto said at the meeting. Spark researchers also tested a drug that inhibits the immune regulator IL-6. They were able to show that treatment in primates reduces the amount of antibodies against AAV envelopes. In mice, the drug reduced immune responses to such an extent that the animals could receive multiple rounds of gene therapy.

“Eventually, a whole package of strategies will likely 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, like the brain, she added. Many inflammation studies have been conducted in the eye, in which researchers can visualize changes that occur months after therapy with relative ease. But “How can we really know what’s going on in the central nervous system or in the ear?” Asked Chan. His concern is that we can delude ourselves for a long time.

About the author


Leave a Comment