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About five years ago, George Church and his new post-doctoral fellow, Ying Kai Chan, sat hunched over a laptop in the genetics pioneer’s office at Harvard, staring in amazement at an old piece of paper.
The paper documented the early trials of Glybera, the first and at the time the only gene therapy approved anywhere on the planet. Fewer than three dozen patients have ever received it, but in the years leading up to Luxturna and Zolgensma, it gave researchers an example they could cite to make gene therapy actually work.
Chan and Church, however, were shocked that researchers in clinical trials had given patients a battery of high-dose immunosuppressive drugs often reserved for organ transplants, names like mycophenolic acid and cyclosporine. And when they biopsied the patients’ muscles, they were filled with T cells, suggesting an immune response in action.
The results were particularly surprising because Glybera used the AAV viral vector, a delivery system that had led to a resurgence of gene therapy precisely because it was generally believed to escape the immune overreaction that has doomed the field in the past. 90s.
Ying Kai Chan“There are so many people working on gene therapy right now and even when you say to them, oh, ‘Did you know cyclosporine was being used? Did you know that all of these things were used? People are like, “Huh, what?” Chan said Endpoints News. “Glybera was the star kid, but it seemed people didn’t appreciate how necessary immunosuppression was.”
Chan trained as a viral immunologist and walked into the Church lab with the intuition that viral vectors, those hollowed out and swollen genetic taxis, were still viruses and still treated by the body as such. Little by little, the ground turned to him. Numerous studies in monkeys have shown that high doses of AAV could be toxic to certain neurons, findings that companies reluctantly accepted. And last year, three deaths in a high-dose trial heightened concerns about the safety of AAVs, although these have not yet been conclusively linked to an immunologic reaction.
During this time, Chan worked on new methods of masking AAV to make it safer and reduce the need for immunosuppressants. This week he, Church, and a larger team at the Wyss Institute published the work in Scientific translational medicine, showing how the weaving of specific strands of human DNA into the vector can neutralize one of the body’s primary defenses against foreign invaders.
“It was very inspired by nature,” Chan said.
One of the first ways that gene therapy pioneer Jim Wilson showed the body could respond to AAV was through a set of sentinels called toll-type receptors. These sentries provide one of the first layers of defense in the immune system, sounding the alarm if they detect something that seems foreign. It does mean, however, that normal cells need a way to tell receptors they are safe – an encryption key that only human cells know.
This encryption key is encoded in a few strands of DNA at the ends of telomeres, those paperclip-shaped strands at the end of chromosomes that are sometimes involved in aging. Chan incorporated these strands into the DNA of an AAV2 vector, the serotype used in Luxturna. When the vector is injected, the strands should bind to toll-type receptors throughout the body and signal the receptors not to sound the alarm.
When the team injected it into the muscles, liver and eyes of pig and mouse models, it triggered a markedly reduced immune response compared to a traditional vector, Chan reported in STM.
The findings add to a series of new technologies emerging from laboratories across the country to combat the immunogenicity of AAVs. Wilson’s lab proposed a way to use microRNAs – short strands that minimize the expression of a particular gene in a given cell – to mitigate neural effects. And Dyno Therapeutics, a Church lab spin-out, is using engineering and machine learning to find entirely new vectors, hoping to find ones that can bypass the immune system.
Chan has now helped start a new company, teaming up with ARCH and a few other VCs to form Ally Therapeutics, an ever-stealthy biotechnology that attempts to minimize the immunogenicity of viral vectors.
Still, he admits he had hoped for more drastic results than he ultimately did. Although its technology was successful in dampening the immune response in pigs and mice, the results were less profound in monkeys.
Chan’s team injected the vector into the eyes of non-human primates, a part of the body that much of the immune system cannot enter, and therefore toll-type receptors are extremely important. They found an improvement in safety when administered under the retina, but direct injection into the vitreous jelly in the center of the eye still triggered significant inflammation. Intravitreal injection is important for fighting several conditions and for making eye gene therapies safer and easier to administer, as only eye surgeons can administer subretinal.
The new document, however, is only version 1.0 of the approach, Chan said, and they’ve made significant improvements since then.
More broadly, the field still has a long way to go. Animal models, for example, are still poor predictors of the immune response in humans, which makes translation difficult and leaves great gaps in safety testing. A vector that appears to be immune-silencing in monkeys could still trigger reactions in humans and vice versa. Although their role in animals is well documented, it is still unclear what role toll-type receptors play in the human response to AAV.
Still, Chan says they accomplished what they set out to do – they improved the vector, and in doing so, helped the field wake up to an issue that has been overlooked for years.
“There are still challenges,” Chan said. “What we really wanted to accomplish was raise awareness and find a promising solution. I would say we have made progress on both fronts.
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