Journal article
Development and evaluation of helper dependent adenoviral vectors for inner ear gene delivery
Hearing research, Vol.435, 108819
08/2023
DOI: 10.1016/j.heares.2023.108819
PMCID: PMC10427999
PMID: 37276687
Abstract
•HdAd is a versatile viral vector with large carrying capacity that can overcome size limitations of adeno-associated virus vectors.HdAd5 transduces multiple cell types within the cochlea including mesenchymal cells, supporting cells and inner hair cells.•HdAd5 transduction varies by delivery route and transduction of cells within the organ of corti is achieved by direct delivery in to the scala media.•HdAd5/35 transduction in the mouse inner ear is CD46 dependent.
Viral vector gene therapy is an attractive strategy to treat hearing loss. Since hearing loss is due to a variety of pathogenic signaling cascades in distinct cells, viral vectors that can express large or multiple genes in a cell-type specific manner are needed. Helper-dependent adenoviral vectors (HdAd) are safe viral vectors with a large packaging capacity (-36 kb). Despite the potential of HdAd, its use in the inner ear is largely unexplored. Therefore, to evaluate the utility of HdAd for inner ear gene therapy, we created two HdAd vectors that use distinct cellular receptors for transduction: HdAd Serotype Type 5 (HdAd5), the Coxsackie-Adenovirus Receptor (CAR) and a chimeric HdAd 5/35, the human CD46+ receptor (hCD46). We delivered these vectors through the round window (RW) or scala media in CBA/J, C57Bl6/J and hCD46 transgenic mice. Immunostaining in conjunction with confocal microscopy of cochlear sections revealed that multiple cell types were transduced using HdAd5 and HdAd 5/35 in all mouse models. Delivery of HdAd5 via RW in the C57Bl/6 J or CBA/J cochlea resulted in transduced mesenchymal cells of the peri‑lymphatic lining and modiolar region while scala media delivery resulted in transduction of supporting cells and inner hair cells. Hd5/35 transduction was CD46 dependent and RW delivery of HdAd5/35 in the hCD46 mouse model resulted in a similar transduction pattern as HdAd5 in the peri‑lymphatic lining and modiolar region in the cochlea. Our data indicate that HdAd vectors are promising vectors for use in inner ear gene therapy to treat some causes of hearing loss.
Details
- Title: Subtitle
- Development and evaluation of helper dependent adenoviral vectors for inner ear gene delivery
- Creators
- Osama Tarabichi - University of IowaTatiana Correa - University of IowaEmre Kul - University of IowaStacia Phillips - University of IowaBahaa Darkazanly - University of IowaSamuel M. Young - University of IowaMarlan R. Hansen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Hearing research, Vol.435, 108819
- DOI
- 10.1016/j.heares.2023.108819
- PMID
- 37276687
- PMCID
- PMC10427999
- NLM abbreviation
- Hear Res
- ISSN
- 0378-5955
- eISSN
- 1878-5891
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/100005380, name: American Neurotology Society; DOI: 10.13039/100006108, name: National Center for Advancing Translational Sciences, award: R03TR004161; DOI: 10.13039/100010475, name: American Society of Pediatric Otolaryngology; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke; DOI: 10.13039/100000055, name: National Institute on Deafness and Other Communication Disorders, award: R01DC012578, R01 DC014093, R01DC018488, R01 NS110742, R21 DC018242, T32 DC000040
- Language
- English
- Date published
- 08/2023
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Anatomy and Cell Biology; Iowa Neuroscience Institute; Neurosurgery; Otolaryngology
- Record Identifier
- 9984426746602771
Metrics
17 Record Views