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  • Mass General Brigham Ventures

Looking to reinvent those troubled AAVs you've been reading about...

Investors back a $110M reboot effort.

Source: EndPoints News

Next week, Affinia Therapeutics will present four new abstracts at the American Society of Gene and Cell Therapy. Though they bear obscure and academic names, they will provide the first proof of concept for an approach investors have now poured $170 million into and that Affinia wants to get in the clinic next year.

Affinia, a 2019 spinout from the lab of old Jim Wilson protégé Luk Vandenberghe, announced Monday that it raised a $110 million Series B led by the biotech VC EcoR1 Capital and the Tom Steyer hedge fund Farallon Capital. Thirteen other investors joined, including the blue-chip firms Atlas, RA Capital, Perceptive Advisors, Casdin Capital, F-Prime and GV.

Affinia is one of a growing number of biotechs trying to solve a problem that has cropped up across the gene therapy field: The adeno-associated viruses (AAVs) that researchers have used to deliver healthy, functional genes into patients to fix maladies ranging from blindness to hemophilia are simply not good enough to do all the things researchers want to do with them, or treat all the diseases they want to treat.

These (mostly) harmless viruses are bad at delivering to many tissues, including common ones implicated in many diseases, like muscle diseases. They are difficult to manufacture. They can only be delivered once. They can’t be delivered to wide swaths of the population. And they can actually only carry genes of a certain size.

So startups are now deploying new techniques to develop new vectors with better qualities. Affinia, for example, will show a new AAV next Thursday that can pass over the liver and go straight to the muscle. That’s important because many AAVs traffic directly to the liver, sometimes leading to dangerous toxicities when companies use high doses.

“That’s just one example of what we believe the field actually needs,” CEO Rick Modi, who previously served as CBO of AveXis, told Endpoints News.

Affinia’s approach to engineering new viruses is distinct from some of its rivals. Dyno Therapeutics, for example, has landed partnerships with Roche, Sarepta and Novartis, with a high-throughput, computation-heavy approach. They make mutations in the DNA code of millions of viruses, screen how the resulting virus behaves in cells and animals, and then use machine learning to examine the results and predict what mutations are beneficial and what mutations are detrimental.

Affinia, by contrast, uses a technique developed by Vandenberghe, who co-discovered the now commonly used AAV9 at Wilson’s lab before starting his own lab at Massachusetts Eye and Ear. The approach is closer to rational design, relying on a much smaller library of better-characterized AAVs, some computation, and their own cell and animal screens.

Feeding protein sequences from different viruses into an evolutionary computer, Vandenberghe was able to reverse engineer “ancestral” forms of the virus and look at where two viruses may have diverged. They can then use that information to build new strains with their desired qualities.

With the latest muscle-adapted virus, for example, Affinia found ancestral AAVs that didn’t hit the liver and then identified 11 different amino acids that may have been responsible for the difference. By screening all the possible changes at those 11 spots, they found a single switch they could make on the 266th slot in the chain of amino acids that makes up an AAV.

The company inserted that switch into a modern AAV so it bypasses the liver. They then added an additional peptide that helps it bind to receptors on muscle.

So far, Affinia has focused on developing AAVs that can better target muscle and the central nervous systems. They have their own internal undisclosed programs, with plans to file an IND next year, and a partnership with Vertex to develop AAVs for, among other diseases, muscular dystrophies — a class of diseases where inefficient vectors have prevented researchers from having as large an impact as they hoped.

Longer term, though, they are also working on other methods to improve gene therapy. That includes developing sequences called promoters that tell AAVs to only express the gene in a specific cell type within a given tissue. There are also plans to make them easier to manufacture and develop new, additional agents that would allow investigators to administer the viruses to patients who can’t receive them today because they’ve been exposed to the virus in the past.

Modi acknowledges he’s not alone in chasing those goals. But the potential payoff is significant, potentially allowing the field to move beyond the rare diseases where it has focused to date.

“If one invests in the basic science: vectors, promoters, pharmacologic agents and manufacturing technologies,” he said, “we can actually go into diseases that are bigger, larger and otherwise would not be able to benefit from a one-time potential cure.”

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