Researcher | Research Overview
The perception of sound in the human inner ear begins in the sensory hair cells of the snail shaped cochlea. Hair cells convert sound vibration into electrical signals, which are transmitted via spiral ganglion neurons through the eighth cranial nerve to the brain. In my lab, we investigate the function of several hair cell genes associated with hearing loss and assess novel therapies to protect or restore auditory function.
We have recently identified central players of the sensory hair cell transduction machinery: the transmembrane channel like, Tmc1 and Tmc2 (Kawashima et al. 2011, Pan et al. 2013). These Tmc molecules are components of the mechanotransduction channel in hair cells of the mammalian inner ear but are differentially expressed during development in the auditory and balance organ. Some of our current work explores how similarity and differences in these two molecules affect cellular and organ physiology and function.
Over 70 genes have been identified that cause hereditary deafness. To explore the broad applicability of inner ear gene therapy, my lab develops tools to tackle genetic deafness that results from mutations in the Usher genes responsible for combined hearing impairment and blindness. Our first study was focused on Usher syndrome type IC using a knock-in mouse model with a cryptic splice site mutation found in French-Acadian USH1C patients. Early postnatal round window membrane injections of synthetic adeno-associated viral vectors (AAVs) carrying the correct Ush1c gene lead to unprecedented recovery of sensory hair cell function and auditory sensitivity as well as balance near wild type level (Pan et al. 2017). The data suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders. We are now continuing this work to assess various gene therapy approaches to target several usher genes.
Researcher | Research Background
Gwenaëlle Géléoc received a PhD, in 1996, from the University of Montpellier II, France. During her PhD, she worked in collaboration with Drs. Corne Kros and Guy Richardson at the University of Sussex in Brighton, UK. She completed a postdoctoral fellowship in the Department of Physiology at University College London with Professor Jonathan Ashmore and subsequently worked as a postdoctoral fellow with Professor David Corey in the Department of Neurobiology at Harvard Medical School. In 2001, she joined the faculty at the University Of Virginia as Assistant Professor of Research and was promoted to Associate in 2007. In the summer of 2011, she returned to Boston and joined the Department of Otolaryngology at Children’s Hospital and Harvard Medical School in the F.M. Kirby Neurobiology Center.
- G.S.G. Géléoc, G.W.T. Lennan, G.P. Richardson, and C.J. Kros (1997) A quantitative comparison of mechano-electrical transduction in vestibular and auditory hair cells of neonatal mice. Proceedings of the Royal Society London, 264: 611–621
- G.S.G. Géléoc and J.R. Holt (2003) Developmental acquisition of sensory transduction in hair cells of the mouse inner ear. Nature Neuroscience, 6 :1019-1020 PMCID: PMC2669437 G.S.G. Géléoc, J.R. Risner and J.R. Holt (2004) Developmental acquisition of voltage dependent conductances and sensory signaling in hair cells of the embryonic mouse inner ear. J Neuroscience, 24:11148-11159. Cover picture of the 2004 Dec 08 Journal issue. PMCID: PMC2638092
- A. Lelli, Y. Asai, A. Forge, J.R. Holt and G.S.G. Géléoc (2009) Tonotopic gradient in the developmental acquisition of sensory transduction in outer hair cells of the mouse cochlea. J Neurophysiology, 101: 2961-2973. PMCID: PMC2694104
- Y. Kawashima*, G.S.G. Géléoc*, K. Kurima*,V. Labay, A. Lelli, Y. Asai, T. Makishima,D.K. Wu, C. C. Della Santina, J.R. Holt, A. J. Griffith (2011). Mechanotransduction in mouse inner ear hair cells requires transmembrane channel–like genes. J. Clinical Investigation, 121(12):4796-809 (*co-first authors) PMCID: PMC3223072
- B. Pan, G.S.G. Géléoc, Y. Asai, G.C. Horwitz, K. Kurima, K. Ishikawa, Y. Kawashima, A.J. Griffith, J.R. Holt (2013). TMC1 and TMC2 Are Components of the Mechanotransduction Channel in Hair Cells of the Mammalian Inner Ear. Neuron. 79(3):504-515 PMCID: PMC3827726
- Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS. (2017) Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017 35:264-272. PMCID: PMC5340578