Transcriptomic Profiling Reveals Divergent Immune Responses to AAV1 and AAV-ie in Mice Inner Ear

TL;DR

This study compares immune responses to two AAV vectors in the inner ear of mice, showing that AAV1 causes milder and later reactions than AAV-ie.

Contribution

The study reveals distinct immune dynamics between AAV1 and AAV-ie, guiding the selection of safer vectors for gene therapy in hearing loss.

Findings

AAV1 induces significantly later immune reactions compared to AAV-ie.

AAV-ie triggers more intense immune responses in the inner ear.

Transcriptomic profiles help identify immunologically optimized AAV vectors.

Abstract

Adeno-associated virus (AAV) unequivocally emerges as one of the most powerful and promising delivery vectors for gene therapy targeting hereditary hearing loss. Following AAV transduction in the inner ear, varying degrees of natural immune responses are triggered, primarily characterized by macrophage activation and the secretion of pro-inflammatory factors. Additionally, the production of neutralizing antibodies may affect the efficacy of gene therapy. To evaluate immune dynamics, we injected AAV1 and AAV-ie (capsids with distinct transfection efficiencies) into murine cochleae and analyzed temporal transcriptomic profiles. Our results demonstrate that both capsids induce immune activity but with critical temporal and intensity differences that AAV1 elicits significantly later and milder immune reactions compared to AAV-ie. These findings establish that dynamic cochlear gene expression profiles directly inform the selection of immunologically optimized AAV vectors to minimize adverse responses in future hereditary hearing loss gene therapies.

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