Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs.

Autor:	Du X; Hough Ear Institute, Oklahoma City, OK 73112, USA., Cai Q; Hough Ear Institute, Oklahoma City, OK 73112, USA; Otologic Pharmaceutics Inc., Oklahoma City, OK 73104, USA., West MB; Hough Ear Institute, Oklahoma City, OK 73112, USA., Youm I; Hough Ear Institute, Oklahoma City, OK 73112, USA., Huang X; Hough Ear Institute, Oklahoma City, OK 73112, USA; Otologic Pharmaceutics Inc., Oklahoma City, OK 73104, USA., Li W; Hough Ear Institute, Oklahoma City, OK 73112, USA., Cheng W; Hough Ear Institute, Oklahoma City, OK 73112, USA., Nakmali D; Hough Ear Institute, Oklahoma City, OK 73112, USA., Ewert DL; Hough Ear Institute, Oklahoma City, OK 73112, USA., Kopke RD; Hough Ear Institute, Oklahoma City, OK 73112, USA; Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Departments of Physiology and Otolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Otologic Pharmaceutics Inc., Oklahoma City, OK 73104, USA. Electronic address: rkopke@houghear.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2018 May 02; Vol. 26 (5), pp. 1313-1326. Date of Electronic Publication: 2018 Mar 10.
DOI:	10.1016/j.ymthe.2018.03.004
Abstrakt:	Deafness is commonly caused by the irreversible loss of mammalian cochlear hair cells (HCs) due to noise trauma, toxins, or infections. We previously demonstrated that small interfering RNAs (siRNAs) directed against the Notch pathway gene, hairy and enhancer of split 1 (Hes1), encapsulated within biocompatible poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) could regenerate HCs within ototoxin-ablated murine organotypic cultures. In the present study, we delivered this sustained-release formulation of Hes1 siRNA (siHes1) into the cochleae of noise-injured adult guinea pigs. Auditory functional recovery was measured by serial auditory brainstem responses over a nine-week follow-up period, and HC regeneration was evaluated by immunohistological evaluations and scanning electron microscopy. Significant HC restoration and hearing recovery were observed across a broad tonotopic range in ears treated with siHes1 NPs, beginning at three weeks and extending out to nine weeks post-treatment. Moreover, both ectopic and immature HCs were uniquely observed in noise-injured cochleae treated with siHes1 NPs, consistent with de novo HC production. Our results indicate that durable cochlear HCs were regenerated and promoted significant hearing recovery in adult guinea pigs through reversible modulation of Hes1 expression. Therefore, PLGA-NP-mediated delivery of siHes1 to the cochlea represents a promising pharmacologic approach to regenerate functional and sustainable mammalian HCs in vivo. (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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