Wilson reports fatal primate toxicity with second AAV9 variant

Gene therapy pioneer James Wilson reported in Molecular Therapy a second instance of a non-human primate death in a pilot study testing high systemic dosing of a variant of adeno-associated viral vector 9, but not in a non-human primate receiving AAV9 itself. The results support the concept that high systemic dosing of AAV can cause severe innate immune reactions, but that the dose threshold for doing so can vary widely by product specific factors.

In the paper released online Feb. 1, Wilson and colleagues administered 7.5x10^13 vector genomes per kg (vg/kg) of AAVs encoding green fluorescent protein (GFP) to adult rhesus macaques; one received the gene encoded by AAV9, and one by PHP.B, a variant of AAV9 selected for enhanced CNS uptake in C57BL/6J mice. The non-human primate receiving PHP.B experienced transaminase elevations, thrombocytopenia and diffuse bleeding that “required euthanasia,” whereas the non-human primate receiving AAV9 experienced transaminase elevations that did not lead to clinical pathologies...