Challenges Stunting The AAV Field

By Tyler Menichiello, contributing editor

Recently, DeciBio conducted a survey among KOLs in the adeno-associated virus (AAV) vector space to identify key pain points in the field. There were 50 respondents, the majority of which were affiliated with biopharma (50%), followed by academia (30%), and CDMOs (20%). Their responses highlight some of the biggest challenges facing the AAV space today. I had the chance to discuss these results with Dr. Carl Schoellhammer, principal at DeciBio, to learn what they mean for the industry moving forward.

The Need For Better Separation And Screening

Respondents indicated that the separation of AAV capsids (full vs. empty vs. partially formed) is the biggest challenge they face, and there’s a strong desire for better tools to do so “If you look at the tools ecosystem — the things that are used to actually make these drugs — it’s largely cobbled together from traditional biologics manufacturing,” Schoellhammer explains. “So, you have these really powerful, potentially curative therapies, and yet on the back end, it’s kind of duct-taped together.”

Not surprisingly, biopharma stakeholders rated separation difficulty much higher than other respondents. This is because “having an incomplete capsid in your drug formulation can kill people,” Schoellhammer says. Separating empty or half-formed AAV capsids from full, complete capsids is essential for ensuring a safe, homogenous product.

Unfortunately, separation costs only get higher at a larger scale, and at some point, the cost outweighs the feasibility. Some survey respondents indicated they could only afford to get their AAV products around 80% pure, which can lead to safety issues. “Right now, it can be too difficult and too expensive to get any better separation, and you’re really going to just kill your drug program by trying.” This lack of efficient separation technology contributes significantly to the high cost of gene therapies.

Respondents also found separation difficulty to be serotype-dependent, with AAV5 considered the most difficult. Schoellhammer says this isn’t too surprising, since it’s one of the most common serotypes and therefore “front-of-mind” for those surveyed. Respondents from biopharma ranked AAVDJ and AAV9 as the most difficult to separate. This makes sense, since a large proportion of CNS-targeting therapies in their pipelines leverage these serotypes.

AAV serotypes can be thought of as different “flavors” or variations capable of targeting certain tissues. “A lot of groups, through directed evolution or modification of existing serotypes, are trying to develop new flavors to try and hit different tissues or different organs more efficiently,” Schoellhammer explains. Researchers doing that kind of work need effective ways of screening these serotypes — to see how well these new "flavors” transduce or “hit” different tissues. Survey respondents indicate that this ability to perform effective multiplex screening is an area of high unmet need.

Roughly 70% of respondents expressed a willingness to try a new functional assay as long as they see publications from other KOLs using it themselves. “You generally don’t see that from a tools perspective; biopharma trying to test a new product or use something,” Schoellhammer says. “That really kind of tells you the need there and the impact to be able to do that kind of work, the likelihood to try new systems like that.” The only respondents who did not express interest in such a product were those actively involved in developing one themselves.

Moving AAVs Forward

Despite these challenges facing the AAV field, Schoellhammer says, the industry is flourishing. Just in the past two months, we’ve seen approvals for the first gene therapies to treat hemophilia and Duchenne Muscular Dystrophy, both of which utilize AAVs for delivery. Schoellhammer thinks these approvals are helping “catalyze the space.” Though both of these indications are monogenic, he thinks the future of AAVs will extend beyond just single gene mutations to much broader delivery. “You’re going to see AAVs being used to deliver CRISPR machinery to do a variety of edits,” he says, “using AAVs as a ‘Mack Truck’ as opposed to just replacing a single gene.”

In order to use AAVs in this capacity, technology has to catch up to their potential. Better screening methods and tools are necessary to develop AAVs that target the right organs. More importantly, from a safety perspective, better tools are needed to ensure efficient and cost-effective separation methods to achieve 100% purity. “If you’re going to broaden AAVs to a wider set of indications, you’re not going to be able to take that gamble on 20% of your separations anymore,” Schoellhammer says. “You’re going to need a clean product.”