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Neonatal Murine Cochlear Explant Technique as an In Vitro Screening Tool in Hearing Research
Published on: June 8, 2017
Viral vector tropism for supporting cells in the developing murine cochlea
Abraham M Sheffield1, Samuel P Gubbels, Michael S Hildebrand
1Department of Otolaryngology, University of Iowa, Iowa City, IA, USA.
Hearing Research
|May 3, 2011
Summary
Bovine adeno-associated virus (BAAV) shows promise for treating genetic hearing loss by safely targeting inner ear supporting cells. This vector delivered therapeutics in utero without causing hearing loss in mice.
Area of Science:
- Otolaryngology
- Gene Therapy
- Developmental Biology
Background:
- Genetic hearing loss is a significant health concern, with connexin 26 mutations causing the most common congenital form (DFNB1).
- Effective gene therapy requires safe and targeted delivery vectors for inner ear cells, particularly supporting cells of the organ of Corti.
- In utero gene delivery is crucial for congenital deafness, necessitating vector evaluation in the developing inner ear.
Purpose of the Study:
- To investigate the in utero tropism and ototoxicity of novel viral vectors in the developing murine inner ear.
- To characterize the potential of early-generation adenovirus, advanced-generation adenovirus, and bovine adeno-associated virus (BAAV) for gene therapy applications.
- To assess the safety and efficacy of BAAV in targeting supporting cell progenitors for potential treatment of genetic hearing loss.
Main Methods:
- Transuterine microinjection of fetal murine otocysts with three viral vectors: Ad5.CMV.GFP, Adf.11D, and BAAV.CMV.GFP.
- Evaluation of viral tropism within the developing cochlea, focusing on organ of Corti supporting cells and spiral ganglion neurons.
- Auditory brainstem response (ABR) testing to assess hearing thresholds and identify potential ototoxicity post-injection.
Main Results:
- Adenovirus vectors demonstrated robust tropism for supporting cells but induced ototoxicity, evidenced by increased ABR thresholds.
- BAAV exhibited tropism for supporting cells, with preferential transduction at the cochlear apex, and also transduced spiral ganglion neurons.
- BAAV-injected mice maintained normal hearing thresholds at 5 weeks of age, indicating a lack of significant ototoxicity.
Conclusions:
- BAAV is a promising vector for safe and efficient gene transfer to supporting cell progenitors in the developing inner ear.
- BAAV offers a potential therapeutic strategy for congenital genetic hearing loss by targeting key cells in the cochlea.
- This study highlights the importance of vector selection for successful inner ear gene therapy and provides evidence for BAAV's suitability.
