Improving Control of Gene Therapy-Based Neurotrophin Delivery for Inner Ear Applications

Abstract

Background: Survival and integrity of the spiral ganglion is vital for hearing in background noise and for optimal functioning of cochlear implants. Numerous studies have demonstrated that supplementation of supraphysiologic levels of the neurotrophins BDNF and NT-3 by pumps or gene therapy strategies supports spiral ganglion survival. The endogenous physiological levels of growth factors within the inner ear, although difficult to determine, are likely extremely low within the normal inner ear. Thus, novel approaches for the long-term low-level delivery of neurotrophins may be advantageous.Objectives: This study aimed to evaluate the long-term effects of gene therapy-based low-level neurotrophin supplementation on spiral ganglion survival. Using an adenovirus serotype 28-derived adenovector delivery system, the herpes latency promoter, a weak, long expressing promoter system, has been used to deliver the BDNF or NTF3 genes to the inner ear after neomycin-induced ototoxic injury in mice.Results: Treatment of the adult mouse inner ear with neomycin resulted in acute and chronic changes in endogenous neurotrophic factor gene expression and led to a degeneration of spiral ganglion cells. Increased survival of spiral ganglion cells after adenoviral delivery of BDNF or NTF3 to the inner ear was observed. Expression of BDNF and NT-3 could be demonstrated in the damaged organ of Corti after gene delivery. Hearing loss due to overexpression of neurotrophins in the normal hearing ear was avoided when using this novel vector–promoter combination.Conclusion: Combining supporting cell-specific gene delivery via the adenovirus serotype 28 vector with a low-strength long expressing promoter potentially can provide long-term neurotrophin delivery to the damaged inner ear.

Recent progress in nanomedicine-mediated cytosolic delivery

“…Some cytosolic delivery methods have been clinically evaluated, approved, and used (Table 2). [67][68][69][70][71] For certain cases in clinical uses, combining those cytosolic delivery methods may be needed to achieve maximized cytosolic delivery. For example, FL, CPPs, and stimuli-sensitive can be combined those techniques on one nanomedicine to target specic cells and subcellular organelles with the highest efficiency.…”

Optimization of pharmacological interventions in the guinea pig animal model—a new approach to calculate the perilymph volume of the scala tympani

“…This requires opening the inner ear, which may lead to side effects such as transient or permanent threshold shifts. Therefore, this delivery approach is currently only used for gene therapy approaches (Staecker et al, 2014;Ramekers et al, 2015;Pfannenstiel et al, 2020;St Peter et al, 2022), which are not yet part of the clinical routine, or in combination with cochlear implantation. In case of the latter, drugs can be injected as a single bolus into the ST followed by insertion of the CI (Paasche et al, 2006;Braun et al, 2011;Prenzler et al, 2018Prenzler et al, , 2020.…”