Immunosuppression reduces rAAV2.5T neutralizing antibodies that limit efficacy following repeat dosing to ferret lungs

• DOI: 10.1016/j.omtm.2023.02.015
• Publication Date: 2023-03-02T07:47:41Z
• Authors: Yinghua Tang; Shahab Fakhari; Eric D. Huntemann; Zehua Feng; Peipei Wu; William Y. Feng; Junying Lei; Feng Yuan; Katherine J. Exco...; Kai Wang; Maria P. Limberis; Roland Kolbeck; Ziying Yan; John F. Engelhardt
• Keywords: Immunosuppression; Adeno-associated virus

The efficacy of redosing the recombinant adeno-associated virus (rAAV) vector rAAV2.5T to ferret lung is limited by AAV neutralizing antibody (NAb) responses. While immunosuppression strategies have allowed for systemic rAAV repeat dosing, their utility lung-directed gene therapy largely unexplored. To this end, we evaluated two (IS) improve dosing lungs: (1) a combination three IS drugs (Tri-IS) with broad coverage against cellular and humoral responses (methylprednisolone [MP], azathioprine, cyclosporine) (2) MP alone, which typically used in applications. Repeat utilized AAV2.5T-SP183-fCFTRΔR (recombinant CFTR transgene), followed 28 days later AAV2.5T-SP183-gLuc (for quantification transgene expression). Both Tri-IS significantly improved expression following reduced AAV2.5T NAb bronchioalveolar lavage fluid (BALF) plasma, while binding subtypes immune ELISpot were unchanged IS. One exception was reduction plasma immunoglobulin G (IgG) both groups. Only strategy suppressed splenocyte IFNA (interferon α [IFN-α]) IL4. Our studies suggest that may be useful clinical application targeting genetic diseases such as cystic fibrosis.