Aldh inhibitor restores auditory function in a mouse model of human deafness

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with aPou4f3gene mutation (Pou4f3 Delta) identical to that found in a familial case of DFNA15. ThePou4f3(Delta/+)mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in thePou4f3(Delta/+)cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of thePou4f3(Delta/+)mice was significantly modified by other genetic and environmental factors. UsingPou4f3(-/+)heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of thePou4f3gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstratePou4f3haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss. Author summary More than 50% of deafness cases are due to genetic defects with no treatment available. DFNA15, caused by mutations of the transcription factorPOU4F3, is one of the most common types of autosomal dominant non-syndromic deafness. Here, we established a novel mouse model with the exactPou4f3mutation identified in human patients. The mutant mouse display similar auditory pathophysiology as human patients and exhibit multiple hair cell abnormalities. The onset and severity of hearing loss in the mouse model is highly modifiable to environmental factors, such as aging, noise exposure or genetic backgrounds. Using a new knockout mouse model, we found Pou4f3 haploinsufficiency as the underlying mechanism of human DFNA15. Importantly, we identified Aldh inhibitor as a potent small molecule for upregulation of Pou4f3 and treatment of hearing loss in the mutant mouse. The identification of Aldh inhibitor for treatment of DFNA15 deafness represents a major advance in the unmet medical need for this common form of progressive hearing loss.