Acta oto-laryngologica · 2025
Cochlear inflammation in AAV-mediated gene therapy: serotype-dependent macrophage activation and promoter-driven immunogenicity.
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Ni Xiaochen, Liu Hongdong, Ji Xiaojun, Chen Zhifeng, Chen Xihang, Luo Yi, Chen Wei, Yang Shiming
Аннотация
BACKGROUND: Recent clinical trials employing AAV (adeno-associated virus)-mediated gene therapy for hereditary deafness have demonstrated significant therapeutic potential. However, immune responses triggered by AAV delivery in the inner ear remain poorly characterized, despite their critical implications for treatment safety and efficacy.
AIMS/OBJECTIVES: This study systematically evaluates serotype-specific (AAV1 vs. AAV9) and promoter-dependent (CMV vs CBA) immune responses in murine cochleae following local AAV delivery.
MATERIALS AND METHODS: Recombinant AAV1/AAV9 vectors expressing tdTomato under CMV or CBA promoters were injected via the posterior semicircular canal. Macrophage infiltration (F4/80+/CD68+ cells) was tracked for five weeks via immunohistochemistry.
RESULTS: Temporal analysis revealed inflammation onset at one week, peaking at two weeks, and resolving to baseline by five weeks. CMV-driven vectors provoked significantly stronger immune activation than CBA. Serotype comparisons showed AAV9 induced greater immunogenicity, with elevated F4/80+ cells at two weeks (p < .001) and prolonged CD68+ cell elevation through four weeks (p < .001) versus AAV1. AAV9 triggered diffuse inflammation, while AAV1 responses were modiolus-restricted.
CONCLUSIONS AND SIGNIFICANCE: These findings highlight serotype- and promoter-dependent immunogenicity as key determinants of cochlear inflammation. Strategic selection of AAV components is essential to balance transduction efficiency and immune tolerance in inner ear gene therapy.
AIMS/OBJECTIVES: This study systematically evaluates serotype-specific (AAV1 vs. AAV9) and promoter-dependent (CMV vs CBA) immune responses in murine cochleae following local AAV delivery.
MATERIALS AND METHODS: Recombinant AAV1/AAV9 vectors expressing tdTomato under CMV or CBA promoters were injected via the posterior semicircular canal. Macrophage infiltration (F4/80+/CD68+ cells) was tracked for five weeks via immunohistochemistry.
RESULTS: Temporal analysis revealed inflammation onset at one week, peaking at two weeks, and resolving to baseline by five weeks. CMV-driven vectors provoked significantly stronger immune activation than CBA. Serotype comparisons showed AAV9 induced greater immunogenicity, with elevated F4/80+ cells at two weeks (p < .001) and prolonged CD68+ cell elevation through four weeks (p < .001) versus AAV1. AAV9 triggered diffuse inflammation, while AAV1 responses were modiolus-restricted.
CONCLUSIONS AND SIGNIFICANCE: These findings highlight serotype- and promoter-dependent immunogenicity as key determinants of cochlear inflammation. Strategic selection of AAV components is essential to balance transduction efficiency and immune tolerance in inner ear gene therapy.