AAVs in Focus at ASGCT: Improved Precision, Targeting Common Diseases

AAV vectors gene therapy

Pictured: Abstract viruses and DNA/Taylor Tieden for BioSpace

Adeno-associated viruses, or AAVs, are the workhorse vector of gene therapies. With the American Society of Gene and Cell Therapy’s (ASGCT) Annual Meeting set to kick off this week, scientists and pharmaceutical executives are gearing up to discuss the latest in capsid development to support a new generation of gene therapies.

Among the goals of the companies in this space is improving precision for safer and more efficacious candidates and developing treatments for diseases that affect bigger patient populations than the rare diseases addressed by currently approved gene therapies.

"The AAV capsid field is making great progress in targeting AAVs to tissues, such as brain and muscle,” said Laura Richman, the chief development officer at Affinia Therapeutics, which will present data on its capsid programs for genetic cardiomyopathies and sporadic ALS. “These advancements have the potential to unlock diseases that are currently not treated.”

Kevin Forrest, cofounder, president and CEO of Kate Therapeutics, which is developing gene therapies for muscle and heart diseases, said he is also looking forward to presenting about capsid advances. “We’re excited about discussions on next-generation gene therapies that have more potency and selectivity for tissues of interest,” Forrest told BioSpace. “This is where the field is going and is really the next ‘big thing.’”

Targeting Larger Patient Populations

Many of the currently approved gene therapies target rare diseases that individually affect fewer than 200,000 people in the U.S. Capsida Biotherapeutics, a gene therapy platform company with several presentations at ASGCT, is currently working on creating capsids to support therapies for diseases with larger patient populations.

“Ultimately, [approved gene therapies have] really only been used in ultra-rare conditions and oftentimes have been administered using quite invasive delivery methods,” Capsida CEO Peter Anastasiou told BioSpace.

The team at Capsida is engineering capsids to cross the blood brain barrier and avoid the liver, Anastasiou said. “By doing so, that basically enables a much wider therapeutic window.” From this platform, Capsida has developed two programs that are on the cusp of entering the clinic: one for a genetic form of epilepsy and the other for a genetic form of Parkinson’s. While these genetic subsets affect a smaller population, it’s estimated that more than 4 million people have either Parkinson’s or epilepsy in the U.S.

“I’m very excited as gene therapy moves from sort of a rare disease space to a more common disease space,” said Capsida Cofounder and Chief Research and Innovation Officer Nick Flytzanis.

Selectivity for Tissues of Interest

One of the main struggles with AAV therapies—and many therapies in general—is hitting affected cells without damaging other types of cells.

In recent years, companies have mainly focused on improving the ability of AAVs to target and express in certain cells—what’s known as delivery and tropism, Flytzanis said. “That’s not a surprise because those were the main areas—not the only, but the main areas—that were necessary to achieve improvements on to broaden the disease space that gene therapy could be applied to.”

At Capsida, the team is engineering capsids to improve tropism in the brain while reducing accumulation in the liver. The challenge is that many of the receptors expressed in the blood-brain barrier (BBB) are also expressed in the liver. But if the team can get it right, it will allow for decreasing the “very high doses that wild-type capsids have leveraged historically in the gene therapy field, which are associated with off-target toxicities,” said cofounder and Chief Technology Officer Nick Goeden.

Capsida cofounder Viviana Gradinaru, whose lab at CalTech spawned the technology that formed the basis of the company, said that a priority now is identifying more blood-brain barrier receptors. Once those receptors are identified, scientists can use AI-enhanced rational engineering to design AAV capsids that can cross the BBB to deliver therapies while steering clear of the liver. “If we know the BBB weak point, we can prepare better.”

Even now, though, Goeden expressed optimism in AAVs becoming more targeted and supporting more efficacious therapies. Talking about Capsida CEO Anastasiou, Goeden said, “Peter’s mantra is that this is the year of execution, and it really is because we have the opportunity to take all these things we’ve innovated and demonstrate in patients that they lead to much better outcomes.”

Mollie Barnes is a freelance science writer based in Los Angeles. Reach her at mollie@100yearsco.com. Follow her on Threads and Instagram @shejustlikedtogo and see more of her work at molliebarnes.contently.com.

Correction (May 6): This article has been updated from its original version to correct that Nick Flytzanis said companies have mainly focused on improving the ability of AAVs to target and express in certain cells, as opposed to replicate in certain cells. BioSpace regrets the error. 

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