Age-related hearing loss (ARHL) or presbycusis, affects over 50% of individuals aged 75 and older, impairing both sound sensitivity and speech comprehension—especially in noisy environments. While hearing aids can address peripheral deficits, central auditory processing remains a major unmet need. The large-conductance calcium-activated potassium (BK) channel plays a critical role in neuronal excitability and auditory processing, making it a promising therapeutic target.
A new biologic, a novel class of 9-amino acid peptides that selectively modulate BK channel activity, was developed for the treatment of hearing loss. The lead compound, LS3, selectively suppresses BK channel gating by modulating the alpha subunit rather than blocking the pore (as shown by HEK293 cell patch-clamp assays and behavioral rescue in BK-null C. elegans.). LS3 is cyclic, highly potent (IC₅₀ in the low picomolar range), and capable of crossing the blood-brain barrier (BBB). A 10µM topical application to the dura in mice reduces spontaneous and sound-evoked presynaptic input to inferior colliculus neurons, and a 1µM unmasks postsynaptic effects that lower auditory thresholds and sharpen receptive fields in aged animals. LS3 can also shuttle small molecules across the BBB, opening new avenues for CNS drug delivery. LS3 specifically lacks smooth-muscle BK activity, reducing potential peripheral side effects and providing a scaffold for tailoring potency and selectivity in disorders involving BK channel dysfunction.
In vivo efficacy of the LS3 peptide in modulating auditory processing in the brain: Both topical and systemic administration of LS3 significantly suppresses sound-evoked activity in the mouse inferior colliculus (IC), a key auditory brain region.