Activation of Kv7.4 in the cochlea as a therapeutic approach in a mouse model of age-reated hearing loss

Age-related hearing loss (ARHL) is the largest contributor to the substantial hearing loss prevalence and is recognized as a significant factor in psychological and medical morbidity. There is thus a tremendous need for a safe and effective pharmacological treatment. The loss of auditory hair cells, consisting of outer hair cells (OHCs) and inner hair cells (IHCs), has been described as the major cochlear pathology of ARHL. The OHC physiology depends largely on functional potassium ion (K+) recycling in the cochlea. One major component of the K+ recycling circuit is the voltage-gated potassium channel of subfamily q, member 1 (Kv7.1), which is localized in the stria vascularis (SV). Loss of KV7.1 has been associated with congenital deafness caused by impaired K+ secretion. Furthermore, OHC survival is linked to the voltage-gated potassium channel of subfamily q, member 4 (Kv7.4), which dominantly determines their membrane potential. Impaired surface expression of Kv7.4 leads to functional impairment and has also been associated with ARHL. Although multiple chemical Kv7 channel openers have been developed as a therapeutic approach, their applicability has not yet been demonstrated in an in vivo model. The aim of the present study was to investigate the effect of pharmacological Kv7.4 channel activation in the senescence-accelerated mouse prone strain 8 (SAMP8) model as a novel therapeutic approach against ARHL. Surprisingly, we observed a significant threshold variability in the auditory decline of SAMP8 mice over age. In search of an underlying cause, age- related OHC loss could not be linked to this threshold variability. However, an altered Kv7.4 expression in OHCs was linked to the SAMP8 auditory threshold variability over age, preceding OHC loss. Pharmacological Kv7.4 channel activation by novel, small- molecule Kv7.4 agonists was then investigated in SAMP8 mice using different routes of administration: ACOU085 was locally via transtympanic application and ACOU082 was systemically administered via topical application. We demonstrated that the locally administered ACOU085 readily diffused into the cochlea and was able to significantly reduce age-related auditory threshold shifts as well as OHC loss in SAMP8 mice. Our findings in an in-vivo mouse model suggest that pharmacological activation of Kv7.4 is a promising approach to prevent and decelerate age-related decline of auditory function and morphological OHC loss linked to ARHL

Age-related hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitutes the third highest risk factor for dementia. Lifetime noise exposure, genetic predispositions for degeneration, and metabolic stress are assumed to be the major causes of ARHL. Both noise-induced and hereditary progressive hearing have been linked to decreased cell surface expression and impaired conductance of the potassium ion channel

Auditory Threshold Variability in the SAMP8 Mouse Model of Age-Related Hearing Loss: Functional Loss and Phenotypic Change Precede Outer Hair Cell Loss

Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (K(V)7.4), which mediates the current I(K,n) crucial for the maintenance of OHC membrane potential, and KCNQ1 (K(V)7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model

A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss

Abstract Age-related hearing loss (ARHL) is the most common sensory impairment mainly caused by degeneration of sensory hair cells in the cochlea with no causal medical treatment available. Auditory function and sensory hair cell survival critically depend on the Kv7.4 (KCNQ4) channel, a voltage-gated potassium channel expressed in outer hair cells (OHCs), with its impaired function or reduced activity previously associated with ARHL. Here, we investigated the effect of a potent small-molecule Kv7.4 agonist on ARHL in the senescence-accelerated mouse prone 8 (SAMP8) model. For the first time in vivo, we show that Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model. Pharmacological activation of Kv7.4 thus holds great potential as a therapeutic approach for ARHL as well as other hearing impairments related to Kv7.4 function

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast

Accepted manuscriptPortuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.CNPq (408313/2016-1), FAPERGS (PRONEX: 16/2551-0000486-2), Hospital de Clínicas de Porto Alegre (FIPE-HCPA), FINEP-CT-INFRA (02/2010) and FAPESP (2013/24633-2). RMR, EIP and PA-P are recipients of National Council of Technological and Scientific Development (CNPq) scholarshipsinfo:eu-repo/semantics/publishedVersio