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Am J Hum Genet. 2016 Jun 2;98(6):1101-1113. doi: 10.1016/j.ajhg.2016.03.028. Epub 2016 May 26.

RNA Interference Prevents Autosomal-Dominant Hearing Loss.

Author information

1
Department of Otolaryngology - Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Molecular & Cellular Biology, Graduate College, University of Iowa, Iowa City, IA 52242, USA.
3
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Nagano 3908621, Japan.
4
Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
5
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
6
Department of Communication Sciences and Disorders, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA.
7
Department of Otolaryngology - Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Molecular & Cellular Biology, Graduate College, University of Iowa, Iowa City, IA 52242, USA; Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: richard-smith@uiowa.edu.

Abstract

Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

PMID:
27236922
PMCID:
PMC4908151
DOI:
10.1016/j.ajhg.2016.03.028
[Indexed for MEDLINE]
Free PMC Article

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