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Health Focus: Will gene therapy come back? Scientists and doctors are trying to make it safer

After years of frustration, genetic research has been revived, with the approval of a few high-quality drugs and a series of promising clinical trial results against genetic diseases, including sickle-cell disease and leukemia.But as researchers try to develop treatments for new conditions, they are also trying to figure out how to deal with the worrying symptoms that immune responses to treatment may impede their efforts – and produce harmful side effects.

Anxiety was a popular topic at the annual meeting of the American Society of Gene and Cell Therapy (ASGCT) in Washington DC, held from 16 to 19 May, as presenters discussed the effects of inflammation on gene therapy and how to reduce it. “Inflammation is related to the study, but we usually do not talk about it,” said Christine Kay, a surgeon at Vitreoretinal Associates in Gainesville, Florida, while discussing genetic disorders for eye disorders. “I’m glad we started.”

Safety has long been a major concern in gene-therapy research, especially after the death of a participant in gene-therapy research and the discovery of cancer-related gene-therapy toward the end of a century of closed clinical trials and led investors to withdrawgrowing field.But this phenomenon has resurfaced over the past decade, and several genetic therapies are approved by regulators around the world to treat conditions including cancer, blindness, and metabolic disorders. “We are on the list of genetic therapists,” Francis Collins, acting science adviser to US President Joe Biden, told the ASGCT conference. “But we still have thousands of diseases that have not yet been diagnosed.”

Immune system interference

Researchers have long speculated about how the immune system might undermine our immune system. Treatment usually relies on the virus to insert the gene into the cells, but if the recipient already has antibodies against the virus, the immune response may interfere with treatment. As a result, participation in genetic testing is usually limited to people who do not have such antibodies.

In many genetic studies, the gene is carried by one of several adeno-related viruses (AAVs), a group of microbes that have been studied in the field for about 40 years. Thousands of people have received AAV-based gene therapy, said Denise Sabatino, a hematology researcher at Philadelphia Children’s Hospital in Pennsylvania, at the conference. Other genetic therapies approved by the US Food and Drug Administration – which include Zolgensma (parvovec ion), treatment for spinal muscular atrophy, and Luxturna (voretigene and parvovec), which treats retinal dystrophy – can rely on these bacteria. .

But as researchers push to treat more conditions and improve the effectiveness of their therapies, “this has become a real and current problem in AAV gene therapy”, says Fraser Wright, a genetic researcher and founder of Spark Therapeutics in Philadelphia, who developed Luxturna, in a meeting. “As we have advanced to AAV dosing in human studies, we have seen the worst and worst events.” Some of those events included death, adds Fraser.

Burning response

The main concern was whether the antibodies against AAV or its burden could impede gene therapy from working or block opportunities to offer multiple doses, Wright said. But more recently, researchers have discovered that antibodies can trigger the production of inflammatory cells, activate cell death mechanisms, and trigger the development of lethal T cells that can direct AAV-containing cells to destroy them.

Researchers at the ASGCT conference reported efforts to address this inflammation at various angles. Some are looking for alternatives to AAVs, and Collins noted that the NIH system for Somatic Cell Genome Editing studies both viral vectors and non-virals. “I think a lot of us are worried about relying on AAV forever, and would like to have things that are probably less risky,” he said.

Some are trying to ‘personalize’ the AAV genome, making it less likely that the immune system will work. For example, in humans, when DNA C is basically traced directly to the genome sequence by base G, it usually carries a chemical group called methyl. AAV has a high percentage of CG groups other than methyl – a red flag that can be present in the immune system. Wright presented data showing that increasing methylation of CG-rich regions reduced the activity of inflammatory-promoting molecules called cytokines. But, he added, there is a potential trade: the same methylation, if used extensively, may also suppress genetic expression, including AAV-carrying therapeutic genes.

The immune system is suppressed

Some are working on ways to suppress harmful immune responses. Genetic therapies are also often given with steroid-like immunosuppressant’s, but there are concerns that such treatments may sometimes not work, and may put recipients at risk of infection. Anastasia Conti, who studies stem cells at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, reported at an ASGCT conference that a drug called anakinra has reduced inflammation caused by genetic engineering. The drug can also improve the effectiveness of gene therapy by reducing the number of fixed blood cells that turn red – meaning they are still alive but have stopped dividing.

At Selecta Biosciences in Watertown, Massachusetts, researchers are making nanoparticles that are designed to take up cells and synthesize a drug called rapamycin that is sometimes used to suppress the immune system after an organ transplant. In non-human animals, the team found that three monthly doses of nanoparticles inhibited antibody responses in AAV protein shell, science chief Kei Kishi.

Source Journal Reference: Heidi Ledford, Gene therapy’s comeback: how scientists are trying to make it safer, Nature News, 2022, doi: https://doi.org/10.1038/d41586-022-01518-0

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