Journal article
Viral vector tropism for supporting cells in the developing murine cochlea
Hearing research, Vol.277(1), pp.28-36
2011
DOI: 10.1016/j.heares.2011.03.016
PMCID: PMC3137760
PMID: 21530627
Abstract
Gene-based therapeutics are being developed as novel treatments for genetic hearing loss. One roadblock to effective gene therapy is the identification of vectors which will safely deliver therapeutics to targeted cells. The cellular heterogeneity that exists within the cochlea makes viral tropism a vital consideration for effective inner ear gene therapy. There are compelling reasons to identify a viral vector with tropism for organ of Corti supporting cells. Supporting cells are the primary expression site of connexin 26 gap junction proteins that are mutated in the most common form of congenital genetic deafness (DFNB1). Supporting cells are also primary targets for inducing hair cell regeneration. Since many genetic forms of deafness are congenital it is necessary to administer gene transfer-based therapeutics prior to the onset of significant hearing loss. We have used transuterine microinjection of the fetal murine otocyst to investigate viral tropism in the developing inner ear. For the first time we have characterized viral tropism for supporting cells following
in utero delivery to their progenitors. We report the inner ear tropism and potential ototoxicity of three previously untested vectors: early-generation adenovirus (Ad5.CMV.GFP), advanced-generation adenovirus (Adf.11D) and bovine adeno-associated virus (BAAV.CMV.GFP). Adenovirus showed robust tropism for organ of Corti supporting cells throughout the cochlea but induced increased ABR thresholds indicating ototoxicity. BAAV also showed tropism for organ of Corti supporting cells, with preferential transduction toward the cochlear apex. Additionally, BAAV readily transduced spiral ganglion neurons. Importantly, the BAAV-injected ears exhibited normal hearing at 5 weeks of age when compared to non-injected ears. Our results support the use of BAAV for safe and efficient targeting of supporting cell progenitors in the developing murine inner ear.
► We deliver viral vectors via transuterine microinjection to the murine otocyst. ► Bovine adeno-associated virus (BAAV) safely transduces the fetal murine cochlea. ► BAAV has tropism for organ of Corti supporting cells and spiral ganglion neurons. ► Adenoviral vectors have tropism for organ of Corti supporting cells. ► Adenoviral vector delivery to the fetal murine cochlea results in ototoxicity.
Details
- Title: Subtitle
- Viral vector tropism for supporting cells in the developing murine cochlea
- Creators
- Abraham M Sheffield - Department of Otolaryngology, University of Iowa, Iowa City, IA, USASamuel P Gubbels - Department of Surgery, Division of Otolaryngology, University of Wisconsin, Madison, WI, USAMichael S Hildebrand - Department of Otolaryngology, University of Iowa, Iowa City, IA, USAStephen S Newton - Department of Otolaryngology, University of Iowa, Iowa City, IA, USAJohn A Chiorini - Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USAGiovanni Di Pasquale - Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USARichard J.H Smith - Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Hearing research, Vol.277(1), pp.28-36
- DOI
- 10.1016/j.heares.2011.03.016
- PMID
- 21530627
- PMCID
- PMC3137760
- NLM abbreviation
- Hear Res
- ISSN
- 0378-5955
- eISSN
- 1878-5891
- Publisher
- Elsevier B.V
- Language
- English
- Date published
- 2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007198502771
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