Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss
Molecular Therapy. 2024-01-01; :
DOI: 10.1016/j.ymthe.2024.01.021
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Mendia C(1), Peineau T(2), Zamani M(3), Felgerolle C(4), Yahiaoui N(4), Christophersen N(5), Papal S(4), Maudoux A(4), Maroofian R(6), Patni P(4), Nouaille S(4), Bowl MR(7), Delmaghani S(4), Galehdari H(3), Vona B(5), Dulon D(2), Vitry S(8), El-Amraoui A(9).
Author information:
(1)Institut Pasteur, Université Paris Cité, INSERM AO06, Institut de l’Audition,
Unit Progressive Sensory Disorders, Pathophysiology and Therapy, 63 rue de
Charenton, 75012 Paris, France; Sorbonne Université, Collège Doctoral, 75005
Paris, France.
(2)Institut de l’Audition and Université de Bordeaux, Laboratoire de
Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, 33076 Bordeaux,
France.
(3)Department of Biology, Faculty of Science, Shahid Chamran University of
Ahvaz, Ahvaz 6135783151, Iran.
(4)Institut Pasteur, Université Paris Cité, INSERM AO06, Institut de l’Audition,
Unit Progressive Sensory Disorders, Pathophysiology and Therapy, 63 rue de
Charenton, 75012 Paris, France.
(5)Institute for Auditory Neuroscience and InnerEarLab, University Medical
Center Göttingen, 37075 Göttingen, Germany; Institute of Human Genetics,
University Medical Center Göttingen, 37075 Göttingen, Germany.
(6)Department of Neuromuscular Diseases, UCL Queen Square Institute of
Neurology, University College London, WC1E 6BT London, UK.
(7)UCL Ear Institute, University College London, 332 Gray’s Inn Road, WC1X 8EE
London, UK.
(8)Institut Pasteur, Université Paris Cité, INSERM AO06, Institut de l’Audition,
Unit Progressive Sensory Disorders, Pathophysiology and Therapy, 63 rue de
Charenton, 75012 Paris, France. Electronic address: .
(9)Institut Pasteur, Université Paris Cité, INSERM AO06, Institut de l’Audition,
Unit Progressive Sensory Disorders, Pathophysiology and Therapy, 63 rue de
Charenton, 75012 Paris, France. Electronic address: .
Hearing loss is a major health concern affecting millions of people worldwide
with currently limited treatment options. In clarin-2-deficient Clrn2-/- mice,
used here as a model of progressive hearing loss, we report synaptic auditory
abnormalities in addition to the previously demonstrated defects of hair bundle
structure and mechanoelectrical transduction. We sought an in-depth evaluation
of viral-mediated gene delivery as a therapy for these hearing-impaired mice.
Supplementation with either the murine Clrn2 or human CLRN2 genes preserved
normal hearing in treated Clrn2-/- mice. Conversely, mutated forms of CLRN2,
identified in patients with post-lingual moderate to severe hearing loss, failed
to prevent hearing loss. The ectopic expression of clarin-2 successfully
prevented the loss of stereocilia, maintained normal mechanoelectrical
transduction, preserved inner hair cell synaptic function, and ensured
near-normal hearing thresholds over time. Maximal hearing preservation was
observed when Clrn2 was delivered prior to the loss of transducing stereocilia.
Our findings demonstrate that gene therapy is effective for the treatment of
post-lingual hearing impairment and age-related deafness associated with CLRN2
patient mutations.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2024.01.021
PMID: 38243601
Conflict of interest statement: Declaration of interests The authors declare no
competing interests.