Josef M. Miller | PubMed Health

PubMed2001

Gene-based therapy for inner ear disease.

Environmental inner ear insults often lead to hair cell injury and loss. Therapeutic measures for the prevention of hair cell loss are currently limited. Several reports have demonstrated the applicability of growth factors for hair cell protection. The goal of the experiments presented here was to assess the protective capability of the human GDNF transgene against noise trauma in the guinea pig cochlea. The left ears of guinea pigs were inoculated with a recombinant adenovirus with a human GDNF insert (Ad.GDNF). Four days later, animals were exposed to noise trauma. One week later, animals were sacrificed and hair cells counted in the left (inoculated) and right (non-inoculated) ears. Auditory brainstem thresholds were measured before the inoculation and just prior to sacrifice. Control groups included inoculation with a reporter gene vector (Ad.lacZ) and Ad.GDNF in normal ears with no noise exposure. The results show that intracochlear inoculation with adenovirus into normal ears does not compromise hair cell counts and ABR thresholds. Both Ad.GDNF and Ad.lacZ vectors can protect the cochlear hair cells and hearing from the noise insult. The difference between the protection afforded by Ad.GDNF and that of the Ad.lacZ vector is not statistically significant. The mechanism of Ad.lacZ protection needs to be elucidated. The data demonstrate the general feasibility of gene therapy for over-expression of neurotrophic factors against noise trauma, and emphasize the complexity of the technique and the problems of variability between subjects.

Journal Article↗

PubMed2001

Absence of hair cell protection by exogenous FGF-1 and FGF-2 delivered to guinea pig cochlea in vivo.

Recent findings that glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and transforming growth factor a can protect the auditory hair cells from acoustic trauma or aminoglycoside ototoxicity in vivo raise the question of whether other neurotrophic factors can also protect the hair cells in vivo. Fibroblast growth factor-2 (FGF-2) can protect hair cells from neomycin ototoxicity in vitro, and in vivo study has shown upregulation of FGF receptor-3 in the cochlea following noise exposure, suggesting that some FGF family members might play a role in protection or repair of the cochlea from damage. We therefore examined if FGF-1 and FGF-2 chronically delivered to the cochlea prior to noise overstimulation can attenuate noise-induced hair cell damage in vivo under conditions in which GDNF and NT-3 were effective. Pigmented female guinea pigs underwent left scala tympani implantation of a microcannula attached to an osmotic pump filled with artificial perilymph only or containing FGFs (10 or 1 mg/ml FGF-1 or 10 mg/ml FGF-2). They were exposed to noise (4 kHz octave band, 115 dB SPL, 5 hr) 4 days after surgery. Threshold shifts 10 days postexposure were essentially equivalent at all frequencies tested across different treatment groups. No significant difference in threshold shifts was observed between the treated and untreated ears in any of the groups. The extent of hair cell damage was also comparable among the different treatment groups. These findings indicate that exogenous FGF-1 or FGF-2 does not influence noise-induced hair cell damage under the experimental conditions used in this study, suggesting that these FGFs are not good candidates as auditory hair cell protectors in vivo.

Journal Article↗