A new immune pathway mediating AAV immune responses

Adeno-associated virus (AAV) gene therapies are gaining momentum in the clinic, with five FDA-approved products as of December 2023 and a broad pipeline of others in clinical testing. However, managing immune responses continue to be critical for safety and efficacy. Several liver-directed clinical trials have observed loss of transgene expression and hence efficacy weeks after AAV dosing, which was associated with CD8+ T cell responses against capsid and increase in liver transaminases. 1 Manno C.S. Pierce G.F. Arruda V.R. Glader B. Ragni M. Rasko J.J. Ozelo M.C. Hoots K. Blatt P. Konkle B. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 2006; 12: 342-347 Crossref PubMed Scopus (1678) Google Scholar Multiple immune sensors and pathways have been implicated in AAV immune responses, and Toll-like receptor 9 (TLR9), which detects CpG motifs in the DNA genome, has been the most substantiated. It is now common practice to limit TLR9 activation. 2 Wright J.F. Quantification of CpG Motifs in rAAV Genomes: Avoiding the Toll. Mol. Ther. 2020; 28: 1756-1758 Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar ,3 Chan Y.K. Wang S.K. Chu C.J. Copland D.A. Letizia A.J. Costa Verdera H. Chiang J.J. Sethi M. Wang M.K. Neidermyer Jr., W.J. et al. Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses. Sci. Transl. Med. 2021; 13eabd3438 Crossref Scopus (92) Google Scholar Excitingly, Sandeep et al.. have now discovered an immune pathway mediating CD8+ T cell responses against transgene product: the interleukin-1 receptor 1 (IL-1R1)-MyD88 signaling axis. 4 Kumar, S., Biswas, M., Arisa, S., Lam, A.K., Piñeros, A., Melero Munoz, M., Kapur, R., Kaisho, T., Xiao, W., and Shayakhmetov, D. TLR9-Independent CD8 T Cell Responses in Hepatic AAV Gene Transfer Through IL-1R1-MyD88 Signaling. Available at SSRN 4418617. Google Scholar