scholarly journals Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model

2021 ◽  
Vol 14 ◽  
Author(s):  
David Oestreicher ◽  
Maria Magdalena Picher ◽  
Vladan Rankovic ◽  
Tobias Moser ◽  
Tina Pangrsic
Keyword(s):  
Gene Therapy ◽  
Hair Cell ◽  
Hearing Impairment ◽  
Hearing Aids ◽  
Calcium Binding ◽  
Cell Function ◽  
Disease Modeling ◽  
Calcium Currents ◽  
Transduction Efficiency ◽  
Inner Hair Cell

Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels CaV1.3. Based on disease modeling in Cabp2–/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC CaV1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2–/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC CaV1.3 function resulting in improved hearing of Cabp2–/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy.

scholarly journals Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish

2014 ◽  
Vol 23 (12) ◽  
pp. 3289-3298 ◽  
Author(s):  
R. L. P. Santos-Cortez ◽  
K. Lee ◽  
A. P. Giese ◽  
M. Ansar ◽  
M. Amin-Ud-Din ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Hair Cell ◽  
Hearing Impairment ◽  
Cell Function

scholarly journals Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258158
Author(s):  
Neil J. Ingham ◽  
Navid Banafshe ◽  
Clarisse Panganiban ◽  
Julia L. Crunden ◽  
Jing Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Cell Function ◽  
Low Frequency ◽  
Mutant Mice ◽  
Auditory Brainstem Responses ◽  
Distortion Product Otoacoustic Emission ◽  
Inner Hair Cell ◽  
Distortion Product ◽  
Age Related

Age-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency recessive hearing impairment in two mutant mouse lines carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation (Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two mutant lines showed similar phenotypes. Threshold for auditory brainstem responses (ABR; a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18lowf mutant mice had abnormally tapering of the tips of inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies.

Novel Mutation in AIFM1 Gene Associated with X-Linked Deafness in a Moroccan Family

2021 ◽  
pp. 1-5
Author(s):  
Soukaina Elrharchi ◽  
Zied Riahi ◽  
Sara Salime ◽  
Hicham Charoute ◽  
Lamiae Elkhattabi ◽  
...  
Keyword(s):  
Hair Cell ◽  
Outer Hair Cell ◽  
Cell Function ◽  
Novel Mutation ◽  
Pedigree Analysis ◽  
Auditory Neuropathy ◽  
Inner Hair Cell ◽  
Whole Exome ◽  
Apoptosis Inducing Factor ◽  
The Impact

<b><i>Introduction:</i></b> Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes. <b><i>Methods:</i></b> We found a disease-segregating mutation in the X-linked <i>AIFM1</i> gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1. <b><i>Results:</i></b> The impact of the c.1045A&#x3e;G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance. <b><i>Discussion/Conclusion:</i></b> To our knowledge, this is the first study that identifies a mutation in the <i>AIFM1</i> gene in Moroccan patients suffering from X-linked auditory neuropathy.

scholarly journals A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

2012 ◽  
Vol 109 (47) ◽  
pp. 19351-19356 ◽  
Author(s):  
A. N. Lukashkin ◽  
P. K. Legan ◽  
T. D. Weddell ◽  
V. A. Lukashkina ◽  
R. J. Goodyear ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hair Cell ◽  
Hearing Impairment ◽  
Inner Hair Cell ◽  
Cell Stimulation

scholarly journals Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss

2021 ◽  
Author(s):  
Neil J Ingham ◽  
Navid Banafshe ◽  
Clarisse Panganiban ◽  
Julia L Crunden ◽  
Jing Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Outer Hair Cell ◽  
Cell Function ◽  
Low Frequency ◽  
Auditory Brainstem ◽  
Auditory Neuropathy ◽  
Mutant Mice ◽  
Inner Hair Cell ◽  
Apical Half

ABSTRACTAge-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency hearing impairment in two mutant mouse lines, carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation (Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two mutant lines showed similar phenotypes. Auditory brainstem response (ABR) thresholds (a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18lowf mutant mice had abnormally tapering inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies. Klhl18 mutant mice exhibit an uncommon low frequency hearing impairment with physiological features consistent with Auditory Neuropathy Spectrum Disorder (ANSD).SIGNIFICANCE STATEMENTWe describe a novel progressive hearing loss in Klhl18 mutant mice that affects the lower frequencies of its’ hearing range. Investigation of two mutant alleles of this gene revealed primary inner hair cell defects affecting the neural output of the cochlea while outer hair cell function appeared normal. The tallest stereocilia of inner hair cells showed an abnormal tapering shape, especially notable in the apical half of the cochlear duct corresponding to the low frequency hearing loss. Our finding of a primary inner hair cell defect associated with raised thresholds for auditory brainstem responses combined with normal outer hair cell function suggests that Klhl18 deficiency and inner hair cell pathology may contribute to Auditory Neuropathy Spectrum Disorder in humans.

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