Vestibular hair cell regeneration and restoration of balance function induced by math1 gene transfer.
OBJECTIVE
Delivery of math1 using an adenovector (Admath1.11D) results in vestibular hair cell regeneration and recovery of balance function in ototoxin-treated adult mice.


BACKGROUND
Loss of peripheral vestibular function is associated with disease processes such as vestibular neuronitis, aminoglycoside ototoxicity, and aging. Loss of vestibular hair cells is one of the mechanisms underlying balance dysfunction in all of these disorders. Currently, recovery from these diseases relies on central vestibular compensation rather than on local tissue recovery. Overexpression of the mammalian atonal homologue math1 has been demonstrated to induce generation of hair cells in neonatal organ of Corti cultures and in the guinea pig cochlea in vivo and could thus provide an approach to local tissue recovery.


METHODS
Admath1.11D was applied to cultures of aminoglycoside-treated macular organs or in vivo in a mouse aminoglycoside ototoxicity model. Outcome measures included histologic examination, immunohistochemistry, swim testing, and evaluation of the horizontal vestibulo-ocular reflex.


RESULTS
Delivery of math1 resulted in the generation of vestibular hair cells in vitro after aminoglycoside-mediated loss of hair cells. Math1-treated mice showed recovery of the vestibular neuroepithelium within 8 weeks after Admath1.11D treatment. Assessment of animals after vector infusion demonstrated a recovery of vestibular function compared with aminoglycoside-only-treated mice.


CONCLUSIONS
Molecular replacement of math1 may provide a therapeutic means of restoring vestibular function related to vestibular hair cell loss.
Staecker
Hinrich
H
Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas 66160, USA. hstaecker@kumc.edu
Praetorius
Mark
M
Baker
Kim
K
Brough
Douglas E
DE
D000617:Aminoglycosides / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006198:Hair Cells, Auditory / Q000276:immunology / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000502:physiology*; D014717:Vertigo / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D020338:Vestibular Neuronitis / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*
D000617:Aminoglycosides; D051792:Basic Helix-Loop-Helix Proteins; C500942:ATOH1 protein, human