In Vivo Delivery of Recombinant Viruses to the Fetal Murine Cochlea: Transduction Characteristics and Long-Term Effects on Auditory Function

Jeffrey C. Bedrosian, Michael Anne Gratton, John V. Brigande, Waixing Tang, Jessica Landau, Jean Bennett

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Congenital hearing deficits can be caused by a variety of genetic and acquired conditions. Complete reversal of deficits in the peripheral auditory system may require delivery of corrective genes to cochlear progenitor cells. We tested delivery of lentivirus and an array of recombinant adeno-associated viral (AAV) serotypes for efficiency and cellular specificity of transgene expression after in utero delivery to the developing mouse otocyst. Stability of expression and safety with respect to auditory function were then tested in those vectors that had the most favorable in utero cochlear transduction characteristics (AAV2/1, AAV2/8, and lentivirus). AAV2/1 was found to be the optimal vector for in utero cochlear gene transfer. It efficiently transduced progenitors giving rise to both inner and outer hair cells and supporting cells and had no adverse effect on cochlear cell differentiation. Further, it had no pathological effect on differentiated hair cells or the integrity of the auditory nerve or brain-stem nuclei as measured by auditory brain-stem response testing. AAV2/1 promises to be useful in further studies evaluating differentiation pathways of cochlear cells in health and disease and for developing gene-based therapies for congenital and acquired forms of peripheral hearing loss.

Original languageEnglish (US)
Pages (from-to)328-335
Number of pages8
JournalMolecular Therapy
Volume14
Issue number3
DOIs
StatePublished - Sep 1 2006

Keywords

  • adeno-associated virus
  • cochlea
  • gene transfer
  • hair cells
  • hearing loss
  • in utero therapy
  • mouse model

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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