Document Detail


Viral vector tropism for supporting cells in the developing murine cochlea.
MedLine Citation:
PMID:  21530627     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Abraham M Sheffield; Samuel P Gubbels; Michael S Hildebrand; Stephen S Newton; John A Chiorini; Giovanni Di Pasquale; Richard J H Smith
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-04-22
Journal Detail:
Title:  Hearing research     Volume:  277     ISSN:  1878-5891     ISO Abbreviation:  Hear. Res.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-15     Completed Date:  2011-11-15     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7900445     Medline TA:  Hear Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  28-36     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier B.V. All rights reserved.
Affiliation:
Department of Otolaryngology, University of Iowa, Iowa City, IA, USA.
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MeSH Terms
Descriptor/Qualifier:
Acoustic Stimulation
Adenoviridae / genetics*
Animals
Audiometry, Pure-Tone
Auditory Threshold
Deafness / genetics,  physiopathology,  therapy*
Dependovirus / genetics*
Evoked Potentials, Auditory, Brain Stem
Gene Transfer Techniques* / adverse effects
Genetic Therapy / adverse effects,  methods*
Genetic Vectors* / adverse effects
Gestational Age
Green Fluorescent Proteins / biosynthesis,  genetics
Labyrinth Supporting Cells / metabolism,  virology*
Mice
Mice, Inbred BALB C
Microinjections
Microscopy, Fluorescence
Organ of Corti / embryology,  metabolism,  physiopathology,  virology*
Stem Cells / virology
Transduction, Genetic
Viral Tropism*
Grant Support
ID/Acronym/Agency:
1UL1RR025011/RR/NCRR NIH HHS; DC003544/DC/NIDCD NIH HHS; G46//Action on Hearing Loss; R01 DC003544-12/DC/NIDCD NIH HHS; R01 DC003544-14/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
147336-22-9/Green Fluorescent Proteins
Comments/Corrections

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