George Church and an entrepreneurial postdoc join the hunt for AAV 2.0 with a new vector-cloaking technology

12 Feb 2021
endpts.com
Gene Therapy
About five years ago, George Church and his new postdoc, Ying Kai Chan, sat hunched over a laptop in the genetics pioneer’s Harvard office and stared in bewilderment at an old paper. The paper documented early trials for Glybera, the first and at the time only gene therapy approved anywhere on the planet. Less than three dozen patients ever received it, but in the years before Luxturna and Zolgensma, it gave researchers an example they could point to for gene therapy actually working. Chan and Church, though, were shocked to see that researchers running 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 patients’ muscles, they were filled with T cells, suggesting an immune response in action. The results were particularly surprising because Glybera used the viral vector AAV, a delivery system that had led to a resurgence in gene therapy precisely because it was commonly believed to evade the immune overreaction that doomed the field in the 90s. “There are so many people working on gene therapy now and even when you tell them, oh, ‘Did you know cyclosporin was used? Did you know all these things were used?’ People are like, ‘Huh, what?” Chan told Endpoints News. “Glybera was the poster child, but it seems people didn’t appreciate how much immunosuppression was required.” Chan trained as a viral immunologist and he came into the Church lab with an intuition that viral vectors, those hollowed out and souped up gene taxis, were still viruses and still treated by the body as such. Gradually, the field has come around to his view. Multiple monkey studies showed that high doses of AAV could be toxic for certain neurons, results that companies have reluctantly accepted. And last year, three deaths in a high-dose trial heightened AAV safety concerns, even if those have yet to be linked conclusively to an immunologic reaction. Meanwhile, Chan has been working on new methods of cloaking 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 Science Translational Medicine , showing how weaving specific strands of human DNA into the vector can neutralize one of the body’s key defenses against foreign invaders. “It was very much inspired by nature,” Chan said. One of the first ways gene therapy pioneer Jim Wilson showed the body could react to AAV was through a set of sentinels called toll-like receptors. These sentinels provide one of the immune system’s first layers of defense, sounding an alarm if they detect anything that appears foreign. That means, though, that normal cells need a way of telling the receptors they’re safe — an encryption key that only human cells know. That encryption key is encoded in a few strands of DNA on the ends of telomeres, those paperclip-shaped strands at the end of chromosomes that are sometimes implicated in aging. Chan incorporated those strands into the DNA of an AAV2 vector, the serotype used in Luxturna. When the vector is injected, the strands should bind to the toll-like receptors throughout the body and tell the receptors not to sound any alarm. When the team injected it into the muscles, liver and eye of pig and mouse models, it triggered a markedly reduced immune reaction than a traditional vector, Chan reported in STM. The results add to a suite of new technologies emerging out of labs across the country to combat AAV immunogenicity. Wilson’s lab has offered a way of using microRNAs — short strands that minimize expression of a particularly gene in a given cell — to mitigate the neural effects. And Dyno Therapeutics, a Church lab spinout, uses engineering and machine learning to come up with wholly new vectors, with the hopes of finding some that can avoid the immune system. Chan has now helped launch a new company, teaming with ARCH and a couple other VCs to form Ally Therapeutics, a still-in-stealth biotech that tries to minimize the immunogenicity of viral vectors. Still, he acknowledges that he had hoped for more sweeping results than he ultimately had. Although his technology successfully tamped down the immune response in pigs and mice, the results were less profound in monkeys. Chan’s team injected the vector into non-human primates’ eyes, a part of the body where much of the immune system can’t enter and, consequently, toll-like receptors are acutely important. They saw improved safety when they administered beneath the retina, but injecting it directly into the vitreal jelly at the center of the eye still triggered significant inflammation. Intravitreal injection is important for tackling several conditions and for more broadly making ocular gene therapies safer and easier to deliver, as only eye surgeons can administer sub-retinally. The new paper, though, is just version 1.0 of the approach, Chan said, and they’ve come up with significant improvements since. More broadly, the field has a long way to go. Animal models, for example, are still poor predictors of the immune response in humans, making translation difficult and putting big holes in safety tests. A vector that appears immune-silent in monkeys could still trigger reactions in humans and vice versa. Although their role in animals is well-documented, it’s still not clear how great a role toll-like 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 the process, helped the field wake up to an issue that for years went overlooked. “There are still challenges,” Chan said. “What we really wanted to accomplish was to raise awareness, as well as come up with a promising solution. I would say we made progress on both fronts.”
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