Abstract
The adeno-associated virus (AAV) gene therapy has been widely applied to mouse models for deafness. But, AAVs could transduce non-targeted organs after inner ear delivery due to their low cell-type specificity. This study compares transgene expression and biodistribution of AAV1, AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB after round window membrane (RWM) injection in neonatal mice. The highest virus concentration was detected in the injected cochlea. AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB transduced both inner hair cells (IHCs) and outer hair cells (OHCs) with high efficiency, while AAV1 transduced IHCs with high efficiency but OHCs with low efficiency. All AAV subtypes finitely transduced contralateral inner ear, brain, heart, and liver compared with the injected cochlea. In most brain regions, the enhanced green fluorescent protein (eGFP) expression of AAV1 and AAV2 was lower than that of other four subtypes. We suggested the cochlear aqueduct might be one of routes for vectors instantaneously infiltrating into the brain from the cochlea through a dye tracking test. In summary, our results provide available data for further investigating the biodistribution of vectors through local inner ear injection and afford a reference for selecting AAV serotypes for gene therapy toward deafness.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.
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Acknowledgements
We thank Z.W. Gao for helping with the manuscript, L. Han for assistance with animal breeding.
Funding
This work was supported by the National Natural Science Foundation of China (82225014, 82171148, and 82192864), the National Key R&D Program of China (2020YFA0908201 and 2021YFA1101302), the Clinical Research Plan of SHDC (SHDC2020CR4083), the Science and Technology Commission of Shanghai (21S11905100), the Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission (20224Z0003), the Shuguang Program of Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (20SG08), and the Medical-Industrial Program of Fudan University, Natural Science Key Project of Scientific Research Innovation Program of Shanghai Education Commission (2023ZKZD12).
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SH, ZX designed and implemented experiments, generated figures, analyzed data, and wrote the manuscript. SH, ZX, and HW performed in RWM injections. SH contributed to hearing tests. ZX, and SW contributed to genomes quantification, SH and ZX contributed to VS-120 microscope and confocal microscopy experiments. HT and SH helped design experiments and write the manuscript. YS, and GG conceived and designed the project, supervised the research, and wrote the manuscript. All authors have reviewed and agreed to the published version of the manuscript.
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Han, S., Xu, Z., Wang, S. et al. Distributional comparison of different AAV vectors after unilateral cochlear administration. Gene Ther 31, 154–164 (2024). https://doi.org/10.1038/s41434-023-00431-z
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DOI: https://doi.org/10.1038/s41434-023-00431-z