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Adeno-associated virus-mediated gene transfer targeting normal and traumatized mouse utricle

Gene Therapy volume 21, pages 958–966 (2014)Cite this article

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Abstract

Balance dysfunction is closely associated with loss of vestibular hair cells (HCs). Gene therapy shows promise when used to protect or regenerate vestibular HCs to preserve or restore adequate vestibular function. Adeno-associated virus (AAV) vectors allow long-term gene expression in the absence of toxicity. To noninvasively define an AAV serotype exhibiting favorable tropism toward the vestibular sensory epithelium, we characterized the transgene expression potential of AAV vectors (serotypes 1, 2, 5, 6 and 8) inoculated into adult mouse utricle via canalostomy. We found that AAV8 was the most effective AAV vector in utricular gene transfer. Swim tests and measurements of auditory brainstem response revealed minimal loss of vestibular function and hearing after canalostomy. In the normal utricle after AAV8 infusion, transduction efficiency peaked at 7 days, and was maintained thereafter, in vestibular HCs, and at 3 days in supporting cells (SCs). In the streptomycin-lesioned utricle, the SC transduction efficiency peaked at 7 days and decreased at 30 days. In conclusion, AAV8-mediated gene transfer via canalostomy facilitates efficient and safe transduction in mouse vestibular sensory epithelium, and may in the future become clinically relevant for human vestibular gene therapy.

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Acknowledgements

This work was supported by the Major State Basic Research Development Program of China (973 Program) (No. 2011CB504503), the National Natural Science Foundation of China (No. 81100717, 81271089 and 81300831), the Technology Development Project of the Beijing Municipal Education Commission (No. KZ201210025026) and the National Science & Technology Pillar Program during the twelfth five-year Plan Period of China (No. 2012BA112B05). We thank Dr Yehoash Raphael for critical comments regarding the manuscript.

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  1. G-P Wang and J-Y Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    G-P Wang, J-Y Guo, Y-Y Liu, J Xie & S-S Gong

  2. Department of Otolaryngology, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Z Peng

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  1. G-P Wang
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Correspondence to S-S Gong.

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Wang, GP., Guo, JY., Peng, Z. et al. Adeno-associated virus-mediated gene transfer targeting normal and traumatized mouse utricle. Gene Ther 21, 958–966 (2014). https://doi.org/10.1038/gt.2014.73

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