Current Knowledge and Further Development in the Field of Otoprotection

26.6K
views
50
authors
8
articles
Editors
3
Impact
Loading...
Original Research
16 September 2022
Development and in vivo validation of small interfering RNAs targeting NOX3 to prevent sensorineural hearing loss
German Nacher-Soler
5 more and 
Francis Rousset

The reactive oxygen species (ROS)-generating enzyme NOX3 has recently been implicated in the pathophysiology of several acquired forms of sensorineural hearing loss, including cisplatin-, noise- and age-related hearing loss. NOX3 is highly and specifically expressed in the inner ear and therefore represents an attractive target for specific intervention aiming at otoprotection. Despite the strong rationale to inhibit NOX3, there is currently no specific pharmacological inhibitor available. Molecular therapy may represent a powerful alternative. In this study, we developed and tested a collection of small interfering (si) RNA constructs to establish a proof of concept of NOX3 inhibition through local delivery in the mouse inner ear. The inhibitory potential of 10 different siRNA constructs was first assessed in three different cells lines expressing the NOX3 complex. Efficacy of the most promising siRNA construct to knock-down NOX3 was then further assessed in vivo, comparing middle ear delivery and direct intracochlear delivery through the posterior semi-circular canal. While hearing was completely preserved through the intervention, a significant downregulation of NOX3 expression in the mouse inner ear and particularly in the spiral ganglion area at clinically relevant levels (>60%) was observed 48 h after treatment. In contrast to successful intracochlear delivery, middle ear administration of siRNA failed to significantly inhibit Nox3 mRNA expression. In conclusion, intracochlear delivery of NOX3-siRNAs induces a robust temporal NOX3 downregulation, which could be of relevance to prevent predictable acute insults such as cisplatin chemotherapy-mediated ototoxicity and other forms of acquired hearing loss, including post-prevention of noise-induced hearing loss immediately after trauma. Successful translation of our concept into an eventual clinical use in humans will depend on the development of atraumatic and efficient delivery routes into the cochlea without a risk to induce hearing loss through the intervention.

4,637 views
6 citations
4,428 views
19 citations
Recommended Research Topics
Frontiers Logo

Frontiers in Cellular Neuroscience

Delivering Therapeutics to the Inner Ear
Edited by Peter S Steyger, Larry Hoffman, Benjamin Shapiro, Sylvain Celanire, Stefan K. Plontke
160.3K
views
99
authors
20
articles
Frontiers Logo

Frontiers in Pharmacology

Identifying Novel Drug Delivery Systems and Treatments for Hearing Loss and Related Ear Disorders, Volume I
Edited by Sho Kanzaki, Konstantina M Stankovic, Myung-Whan Suh, Taro Yamaguchi
44.6K
views
67
authors
9
articles
Frontiers Logo

Frontiers in Neurology

Acute Unilateral Vestibulopathy: Clinical Presentation, Instrumental Patterns, Evolution and Management
Edited by Salvatore Martellucci, Andrea Castellucci, Dario Andres Yacovino, Marco Mandalà, Augusto Pietro Casani
45.1K
views
83
authors
12
articles
Frontiers Logo

Frontiers in Pharmacology

Identifying Novel Drug Delivery Systems and Treatments for Hearing Loss and Related Ear Disorders, Volume II
Edited by Sho Kanzaki, Taro Yamaguchi, Myung-Whan Suh
23.7K
views
39
authors
7
articles
Frontiers Logo

Frontiers in Neurology

The Vestibular System: A tribute to Professor Dr. Hans Straka
Edited by Mathieu Beraneck, Joel C Glover, Andreas Zwergal, François M Lambert, Soroush G Sadeghi
29.2K
views
61
authors
16
articles