Gene therapy pioneer James Wilson’s revelation of two new types of toxicity in animals receiving high systemic doses of adeno-associated viral vectors is unlikely to herald a major disruption of the AAV space, though it remains to be seen whether they influenced his decision to resign as SAB chair of Solid Biosciences Inc.
Wilson plus five AAV researchers who spoke with BioCentury concurred that any repercussions likely would be limited to a handful of products given at high systemic doses to treat neurological or musculoskeletal disorders in children.
The threshold for safe dosing will likely depend on product-specific characteristics.
“The overwhelming majority of gene therapy applications that are being considered in the clinic I don’t think are really impacted by these findings,” Wilson told BioCentury.
“The overwhelming majority of gene therapy applications that are being considered in the clinic I don’t think are really impacted.”
Wilson’s lab group from the University of Pennsylvania presented the animal findings in a Jan. 30 publication in Human Gene Therapy.
Wilson told BioCentury the toxicities arose when his group pushed AAV doses beyond the norm of most therapeutic applications to test the safety of the high vector quantities needed to reach large amounts of muscle or cross the blood-brain barrier.
In particular, the researchers saw a liver toxicity unlike that customarily seen with AAVs because it was accompanied by systemic inflammation and coagulopathy. Both conditions were features of the pathology that led to the death of Jesse Gelsinger in a 1999 gene therapy trial at UPenn, where Wilson is a professor and director of the gene therapy program.
Rather than abandon the therapies altogether, Wilson and the researchers contacted by BioCentury suggested the field should take a more cautious approach to human development while work continues to identify the threshold of toxicity.
Eventually, engineering improvements to vectors to deliver the transgene more efficiently to the target tissue or with less immunogenicity could reduce the risk that newer AAVs will cross that threshold.
It’s unclear the extent to which Wilson’s findings may apply to Solid, which is developing its SGT-001 gene therapy to treat Duchenne muscular dystrophy (DMD).
SGT-001 is delivered by a serotype AAV9 vector designed to stabilize the dystrophin glycoprotein complex by delivering microdystrophin. It is one of three AAVs delivering versions of dystrophin that entered human trials toward the end