A Glucocorticoid Reduces Adverse Effects of Adenovirus Vectors in the Cochlea

Abstract

Gene transfer using a recombinant adenovirus is a powerful tool for research and clinical applications, but its cytotoxicity and immune response limit its use, especially when repeated application of the vector is necessary. This study investigated the effects of dexamethasone (DEX)-induced immunosuppression on the outcome of adenovirus gene transfer in guinea pig inner ears. Animals received DEX for 29 days. Their inner ear was inoculated with 5 µl of adenovirus vector twice, on days 5 and 26. Auditory brainstem response was measured on days 1, 8 and 29. The animals were sacrificed on day 29, and reporter gene expression was evaluated. In control animals that received no DEX, postinoculation threshold shifts and lesions in the organ of Corti were observed and reporter gene expression was absent. In contrast, DEX-treated ears were largely protected, and transduction of inner ear cells was readily apparent. These data demonstrate that immunosuppressive treatment can reduce the negative consequences of repeated adenovirus-mediated gene therapy.

Inner Ear Therapy for Neural Preservation

“…Persistence of transgene expression varied considerably from 5 days to 8-24 weeks [Lalwani et al, 1998a;Li Duan et al, 2002;Praetorius et al, 2002;Wareing et al, 1999], depending partly on the method of delivery (24 weeks continual delivery yielded 24 weeks of expression, but such lengthy transgene delivery caused cochlear cells to die or degrade [Lalwani et al, 1998a]). Repeated single doses of gene therapy were also cytotoxic to HCs, but this was largely due to the immune response and was reduced by co-treatment with the glucocorticoid dexamethasone [Ishimoto et al, 2003].…”

Stable release of BDNF from the fibroblast cell line NIH3T3 grown on silicone elastomers enhances survival of spiral ganglion cells in vitro and in vivo

“…However, they involve potential toxicity and infection risk (Ishimoto et al, 2002(Ishimoto et al, , 2003.…”

Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

“…Direct cochlear infusion of BDNF and other neurotrophic factors using mini-osmotic pumps allows regulation of the duration and quantity of infusion, but their use increases surgical complexity. Viral vectors may be advantageous for long term production of BDNF in the cochlea, but their use involves risk of immune response and toxicity, especially when used for the second time (Ishimoto et al, 2003), limiting the potential for safe clinical application of this technology in humans. Alternative approaches for delivering growth factors in combination with the implanted electrode need to be developed and tested.…”