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Adeno-associated virus-mediated gene delivery into the scala media of the normal and deafened adult mouse ear

Gene Therapy volume 18, pages 569–578 (2011)Cite this article

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Abstract

Murine models are ideal for studying cochlear gene transfer, as many hearing loss-related mutations have been discovered and mapped within the mouse genome. However, because of the small size and delicate nature, the membranous labyrinth of the mouse is a challenging target for the delivery of viral vectors. To minimize injection trauma, we developed a procedure for the controlled release of adeno-associated viruses (AAVs) into the scala media of adult mice. This procedure poses minimal risk of injury to structures of the cochlea and middle ear, and allows for near-complete preservation of low and middle frequency hearing. In this study, transduction efficiency and cellular specificity of AAV vectors (serotypes 1, 2, 5, 6 and 8) were investigated in normal and drug-deafened ears. Using the cytomegalovirus promoter to drive gene expression, a variety of cell types were transduced successfully, including sensory hair cells and supporting cells, as well as cells in the auditory nerve and spiral ligament. Among all five serotypes, inner hair cells were the most effectively transduced cochlear cell type. All five serotypes of AAV vectors transduced cells of the auditory nerve, though serotype 8 was the most efficient vector for transduction. Our findings indicate that efficient AAV inoculation (via the scala media) can be performed in adult mouse ears, with hearing preservation a realistic goal. The procedure we describe may also have applications for intra-endolymphatic drug delivery in many mouse models of human deafness.

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Acknowledgements

We thank Vinu Jyothi for her assistance in ototoxic drug exposure and ABR measurements; Manna Li, Juhong Zhu, Nancy Smythe and James Nicholson for their help with histological observations; Bradley A Schulte and Richard A Schmiedt for their critical comments and invaluable discussion over the course of this study. This study was supported by the National Institutes of Health; grant number: DC00422 (HL); grant number: DC07506 (HL); grant number: DC00713 (BAS); grant number: DC002756 (DMF); American Academy of Otolaryngology–Head and Neck Surgery; grant number: CORE 130165 (LAK).

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Authors and Affiliations

  1. Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA

    L A Kilpatrick & J Yang

  2. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

    Q Li & H Lang

  3. House Ear Clinic, Los Angeles, CA, USA

    J C Goddard

  4. Department of Biology Science, Purdue University, Lafayette, IN, USA

    D M Fekete

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  1. L A Kilpatrick
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Correspondence to H Lang.

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Kilpatrick, L., Li, Q., Yang, J. et al. Adeno-associated virus-mediated gene delivery into the scala media of the normal and deafened adult mouse ear. Gene Ther 18, 569–578 (2011). https://doi.org/10.1038/gt.2010.175

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