Hearing Loss Treatment Report

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KCNQ4

miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates sensorineural hearing loss

CATEGORY:
Research

SCREENSHOT:
miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model

TITLE:
miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model

CONTENT:
J Physiol Sci. 2021 Sep 3;71(1):28. doi: 10.1186/s12576-021-00814-0.

ABSTRACT

Damage to the cochlear sensory epithelium is a key contributor to noise-induced sensorineural hearing loss (SNHL). KCNQ4 plays an important role in the cochlear potassium circulation and outer hair cells survival. As miR-153 can target and regulate KCNQ4, we sought to study the role of miR-153 in SNHL. 12-week-old male CBA/J mice were exposed to 2-20 kHz broadband noise at 96 dB SPL to induce temporary threshold shifts and 101 dB SPL to induce permanent threshold shifts. Hearing loss was determined by auditory brainstem responses (ABR). Relative expression of miR-153 and KCNQ4 in mice cochlea were determined by Real-Time quantitative PCR. miR-153 mimics were co-transfected with wild type or mutated KCNQ4 into HEK293 cells. Luciferase reporter assay was used to validate the binding between miR-153 and KCNQ4. AAV-sp-153 was constructed and administrated intra-peritoneally 24- and 2-h prior and immediately after noise exposure to knockdown miR-153. The KCNQ4 is mainly expressed in outer hair cells (OHCs). We showed that the expression of KCNQ4 in mice cochlea was reduced and miR-153 expression was significantly increased after noise exposure compared to control. miR-153 bound to 3’UTR of KNCQ4, and the knockdown of miR-153 with the AAV-sp-153 administration restored KCNQ4 mRNA and protein expression. In addition, the knockdown of miR-153 reduced ABR threshold shifts at 8, 16, and 32 kHz after permanent threshold shifts (PTS) noise exposure. Correspondingly, OHC losses were attenuated with inhibition of miR-153. This study demonstrates that miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates SNHL. Our study provides a new potential therapeutic target in the prevention and treatment of SNHL.

PMID:34479475 | DOI:10.1186/s12576-021-00814-0

SOURCE:
The journal of physiological sciences : JPS

PUBLISHER:

PMID:
pubmed:34479475

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34479475

DOI:
10.1186/s12576-021-00814-0

DATE – PUBLISHED:
Sat, 04 Sep 2021 06:00:00 -0400

DATE – DOI:
2021-09-03T15:08:12Z

DATE – ADDED:
09/04/21 09:14AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34479475/

LINK – DOI:
https://doi.org/10.1186/s12576-021-00814-0

LINK – PUBLISHER:
https://jps.biomedcentral.com/articles/10.1186/s12576-021-00814-0?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-09-04T13:14:45+00:00, https://www.hearinglosstreatmentreport.com.

KCNQ4 Activators as a Potential Treatment for Hearing Loss

A recently published special issue of International Journal of Molecular Science reviewed a variety of therapeutic interventions currently being studied as novel strategies to restore hearing.

One of these strategies involves the use of “KCNQ4 activators” as a way to keep the inner ear functioning properly. And according to the paper, existing drugs (or combinations thereof) that are already approved could potentially be repurposed as therapies for sensorineural hearing loss.

From the May 26, 2021 paper titled, “Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics”:

The voltage-gated potassium channel KCNQ4 has an essential role in regulating auditory function in the inner ear, by contributing to potassium recycling and maintenance of cochlear homeostasis. Reduced activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss. Rim and colleagues presented a comprehensive review of 90 publications looking at the KCNQ4 as a potential therapeutic target for the treatment of hearing loss. In this review, the authors updated the current concepts of the physiological and pathophysiological roles of KCNQ4 in the inner ear and focused on the role of KCNQ4 activators in therapeutic management of different forms of hearing loss. They propose that the simultaneous application of two activators with distinct modes of action may result in synergistic effects and reduced off-target effects. It was also suggested that drug repurposing may be an attractive option for clinical development of KCNQ4 activators as therapies for hearing loss.

Another recent paper, from three months ago (published March 2, 2021) titled, “Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss”, stated:

Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss.

The authors concluded by recommending that “KCNQ4 activators should be validated in clinical trials, as there is no ongoing clinical trial targeting hearing loss by KCNQ4 activators currently.”

But do not let the fact that KCNQ4 activators have not yet entered human clinical trials mislead you. Despite the current lack of trials, that does not automatically mean these drugs are far, far away.

Because, as the authors also pointed out earlier in the same paper: “Drug repurposing and optimization for applicable specific KCNQ4 mutation might also be an option for clinical application of KCNQ4 activators […] with advantages of reducing the cost and shortening the time when compared to de novo drug discovery.”

As far as what to keep an eye out for next, on the topic of KCNQ4, the researchers also tip us off as to which company is working on this mechanism most closely:

Acousia Therapeutics, which is a biotech company aiming for the development of small-molecule drugs for sensory neuronal hearing loss, has eight compounds targeting KCNQ4 in its pipeline.

Company website here (comment: Acousia seems to keep a low profile, so for now don’t expect to find any additional details about these eight compounds): http://www.acousia.com/

Last but not least, a fun fact.

Aside from the repurposed drugs that might hold hearing restoration potential, there is another compound related to KCNQ4 mentioned in the paper. An exotic one, as described in one of the cited papers: Subtype-Selective Activation of Kv7 Channels by AaTXKβ(2–64), a Novel Toxin Variant from the Androctonus australis Scorpion Venom.

Scorpion venom. Hmmm…

AUTHOR’S NOTE: There is something oddly reassuring about the thought of researchers from around the world leaving no stone unturned (and no tiny venomous creature unexamined) in search of a potential hearing loss cure.

A good reminder that we never know where (or from what) the next big discovery will arise. Nature is full of secrets and science is constantly uncovering these surprises…

KCNQ4 activators meme hearing loss scorpion

More updates to follow…

How to get KCNQ4 activator updates

  • Join the free email newsletter to get updates related to repurposed drugs targeting KCNQ4 (plus, news about other promising treatments in development for hearing restoration). Expect between 1 and 3 emails per week. But only when something interesting appears on the radar. No spam, no promotional emails, no third parties, and one-click unsubscribe. Privacy respected.

References

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

TITLE:
Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

CONTENT:
Int J Mol Sci. 2021 Mar 2;22(5):2510. doi: 10.3390/ijms22052510.

ABSTRACT

Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss.

PMID:33801540 | DOI:10.3390/ijms22052510

SOURCE:
International journal of molecular sciences

PUBLISHER:

PMID:
pubmed:33801540

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33801540

DOI:
10.3390/ijms22052510

DATE – PUBLISHED:
Sat, 03 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-03-03T02:30:13Z

DATE – ADDED:
04/03/21 05:12PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33801540/

LINK – DOI:
https://doi.org/10.3390/ijms22052510

LINK – PUBLISHER:
https://www.mdpi.com/1422-0067/22/5/2510/htm
https://www.mdpi.com/1422-0067/22/5/2510?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-03T21:12:02+00:00, https://www.hearinglosstreatmentreport.com.