Novel small molecule-mediated restoration of the surface expression and anion exchange activity of mutated pendrin causing Pendred syndrome and DFNB4.

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2-1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2-1 significantly increased the surface expression of pendrin. PC2-1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2-1 concentration (30 μM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2-1. In conclusion, PC2-1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.