Genetic and pharmacological intervention for treatment/prevention of hearing loss

Abstract

Twenty years ago it was first demonstrated that birds could regenerate their cochlear hair cells following noise damage or aminoglycoside treatment. An understanding of how this structural and functional regeneration occurred might lead to the development of therapies for treatment of sensorineural hearing loss in humans. Recent experiments have demonstrated that noise exposure and aminoglycoside treatment lead to apoptosis of the hair cells. In birds, this programmed cell death induces the adjacent supporting cells to undergo regeneration to replace the lost hair cells. Although hair cells in the mammalian cochlea undergo apoptosis in response to noise damage and ototoxic drug treatment, the supporting cells do not possess the ability to undergo regeneration. However, current experiments on genetic manipulation, gene therapy, and stem cell transplantation suggest that regeneration in the mammalian cochlea may eventually be possible and may 1 day provide a therapeutic tool for hearing loss in humans.Learning outcomes-The reader should be able to: (1) Describe the anatomy of the avian and mammalian cochlea, identify the individual cell types in the organ of Corti, and distinguish major features that participate in hearing function, (2) Demonstrate a knowledge of how sound damage and aminoglycoside poisoning induce apoptosis of hair cells in the cochlea, (3) Define how hair cell loss in the avian cochlea leads to regeneration of new hair cells and distinguish this from the mammalian cochlea where there is no regeneration following damage, and (4) Interpret the potential for new approaches, such as genetic manipulation, gene therapy and stem cell transplantation, could provide a therapeutic approach to hair cell loss in the mammalian cochlea.

Tinnitus

“…These factors are known to cause death of cochlear hair cells by apoptosis rather than necrosis. 103 Apoptosis can potentially be blocked either before exposure to the injurious agent or for a short period afterwards. Research is therefore continuing to try to fi nd agents that can block apoptosis.…”

“…104,105 Repair of cochlear damage by use of gene therapy and stem cell therapy is also being studied. 103 …”

Morphological and morphometric characterization of direct transdifferentiation of support cells into hair cells in ototoxin-exposed neonatal utricular explants

“…A small, but significant, spontaneous renewal of HCs was demonstrated in the vestibular sensory epithelia of several mammalian species, in vivo for the guinea-pig, chinchilla and mouse, and in vitro for the rat, following an ototoxic injury (Berggren et al, 2003;Kawamoto et al, 2009;Tanyeri et al, 1995). DT of SCs into HCs without a preceding mitotic stage was shown to be the mechanism during renewal of mammalian HCs both in vitro and in vivo renewal (Cotanche, 2008;Izumikawa et al, 2005;Staecker et al, 2007). Transcription factors (TFs) participate during normal development but also have the capacity to induce DT of SCs into HCs (Schimmang, 2013).…”

Morphological and morphometric characteristics of vestibular hair cells and support cells in long term cultures of rat utricle explants

“…In contrast to the major process of HC regeneration in the avian inner ear (i.e. SC proliferation followed by HC and SC differentiation), renewal of mammalian HCs is thought to emerge solely from SCs that transdifferentiate into HCs without any preceding mitotic stage (Kopke et al, 2001;Izumikawa et al, 2005;Staecker et al, 2007;Cotanche, 2008).…”