The Opportunities and Challenges of Gene Therapy for Treatment of Inherited Forms of Vision and Hearing Loss.

Inherited forms of blindness and deafness are highly prevalent and severe conditions that significantly impact the lives of millions of people worldwide. The lack of therapeutic options for these conditions poses a major socioeconomic burden. Over the last decades, gene therapy has proven to be a life changing treatment for hereditary and acquired forms of diseases, and extensive preclinical investigation in animal models of both retinal and inner ear disorders has highlighted promising translational opportunities for these disorders too.

Genetic Medicine for Hearing Loss: OTOF as Exemplar.

Millions of people worldwide have disabling hearing loss because one of their genes generates an incorrect version of some specific protein the ear requires for hearing. In many of these cases, delivering the correct version of the gene to a specific target cell within the inner ear has the potential to restore cochlear function to enable high-acuity physiologic hearing. Purpose: In this review, we outline our strategy for the development of genetic medicines with the potential to treat hearing loss.

Formulations for trans-tympanic antibiotic delivery.

We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs--bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo.

Effect of chemical permeation enhancers on nerve blockade.

Chemical permeation enhancers (CPEs) have the potential to improve access of local anesthetics to the nerve, thereby improving nerve block performance. We assessed the effects of six CPEs on nerve blockade from tetrodotoxin (TTX) and from bupivacaine. Each of the six surfactants, representing three CPE subgroups (anionic, cationic, and nonionic surfactants) was coinjected with TTX or bupivacaine at the sciatic nerve of Sprague-Dawley rats.

Dopaminergic innervation of the mouse inner ear: evidence for a separate cytochemical group of cochlear efferent fibers.

Immunostaining mouse cochleas for tyrosine hydroxylase (TH) and dopamine beta-hydroxylase suggests that there is a rich adrenergic innervation throughout the auditory nerve trunk and a small dopaminergic innervation of the sensory cell areas. Surgical cuts in the brainstem confirm these dopaminergic fibers as part of the olivocochlear efferent bundle. Within the sensory epithelium, TH-positive terminals are seen only in the inner hair cell area, where they intermingle with other olivocochlear terminals expressing cholinergic markers (vesicular acetylcholine transporter; VAT).