The return of gene therapy: How to make treatment safer

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

“I’m a big fan of dose reduction”(Ying Kai Chan, Immunologist)

Some researchers are trying to “humanize” the AAV genome to make it less likely to trigger certain immune responses in the body. For example, when base C DNA is followed directly by 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 signal for the immune system. Wright presented data showing that increasing methylation of CG-rich regions reduces the activation of proinflammatory molecules called cytokines. However, he also mentioned a potential disadvantage: the same methylation, if too present, could also suppress gene expression, including the therapeutic gene carried by AAV.

Limit your immune system

Other research groups are working on ways to suppress harmful immune responses. Gene therapies are often given in conjunction with immunosuppressants such as steroids. However, there are concerns that treatment may be ineffective and recipients were more susceptible to infection. Anastasia Conti, who studies stem cells at the San Raffaele Telethon Institute for Gene Therapy in Milan, said at an ASGCT meeting that the drug anakinra reduces inflammation caused by gene changes. Anakinra could also increase the effectiveness of genome modification treatment by reducing the number of altered blood stem cells that have stopped dividing.

At Selecta Biosciences in Watertown, Massachusetts, researchers are developing nanoparticles that can be loaded with rapamycin and absorbed by immune cells. This drug is sometimes used to suppress the immune system after organ transplantation. Leading scientist Kei Kishimoto said at the meeting that his team found in primates that three monthly doses of packaged nanoparticles prevented antibody reactions to the AAV protein envelope. Spark researchers have also tested a drug that inhibits the immune regulator IL-6. They have shown that treatment in primates reduces the amount of antibodies against AAV envelopes. In mice, the drug reduced immune responses to such an extent that animals could receive more rounds of gene therapy.

“In the end, a number of strategies are likely to be needed to bring 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 inflammations in hard-to-reach parts of the body, such as the brain, he added. Many studies of inflammation have been performed in the eye, where scientists can relatively easily visualize the changes that occur months after therapy. But, “How do we really know what’s going on in the central nervous system or in the ear?” Chan asked. He wants to be able to lie for a long time.

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