Defective HSV-1 vector expressing BDNF in auditory ganglia elicits neurite outgrowth: Model for treatment of neuron loss following cochlear degeneration

M. D. Geschwind, C. J. Hartnick, W. Liu, J. Amat, T. R. Van De Water, H. J. Federoff

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

The neurotrophins are a family of growth factors that play an important role in the development and maintenance of the nervous system. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that appears to participate in the maturation and function of mammalian auditory neurons. Forms of deafness due to varied injurious stimuli that are amenable to treatment with implantable prosthetic devices require the survival of these BDNF-responsive auditory neurons for effective outcome. To evaluate the feasibility of developing a gene therapy for deafness that may be used in conjunction with a prosthetic device, we constructed replication-defective herpes simplex virus (HSV) amplicon vectors that carry the human BDNF cDNA. Using these vectors, HSVbdnf and HSVbdnflac (expresses BDNF and Escherichia coli β-galactosidase), we evaluated the expression and biological activity in established cell lines and explant cultures prepared from spiral ganglia of the murine ear. Gene transfer with HSVbdnf resulted in the efficient expression of human BDNF mRNA in murine fibroblasts. Using two BDNF-responsive cell lines, PC12trkB and MG87trkB, we demonstrate efficient secretion of biologically active BDNF. Finally, transduction of explanted spiral ganglia with HSVbdnflac elicited robust neuritic process outgrowth comparable to exogenously added BDNF. Overall, these data demonstrate that HSV vectors can efficiently transfer and express the BDNF gene in many cell types, including auditory neurons. Moreover, they suggest that similar vectors may be used to express the neurotrophin in auditory neurons in vivo and perhaps as adjunctive gene therapy for deafness.

Original languageEnglish (US)
Pages (from-to)173-182
Number of pages10
JournalHuman gene therapy
Volume7
Issue number2
DOIs
StatePublished - Jan 20 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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