Advances in Small Molecule Candidate-Therapeutics for Hair Cell Regeneration

By June 7, 2019

McLean, Will J.1,2; Loose, Chris1; LeBel, Carl1
1 Frequency Therapeutics, Woburn, MA and Farmington, CT, USA;
2 Department of Surgery, University of Connecticut School of Medicine, Farmington, CT, USA.

Hearing loss is commonly caused by loss of cochlear sensory hair cells after noise or other trauma. Currently, only devices (e.g. hearing aids) exist to treat hearing loss, which do not restore the underlying cellular deficit that causes the disease. Unlike other species, mammals lack the ability to regenerate hair cells. Although previous work showed that mammals have putative hair cell progenitors after cochlear development is complete, these cells fail to divide and differentiate on their own to repair damaged tissue.

Cochlear hair cell progenitors, which express the Wnt pathway protein Lgr5, were isolated from mice and cultured in a 3D organoid culture system. Individual and combinations of compounds were screened to test promotion of progenitor cell proliferation and subsequent differentiation into hair cells. A compound combination that promoted proliferative behavior was tested on isolated intact cochleae ex vivo for its ability to promote new hair cell formation.

A combination of two compounds that activate the Wnt pathway and inhibit histone deacetylase (HDAC) was found to greatly expand otherwise senescent cochlear hair cell progenitors. This combination generated additional hair cells in intact cochleae ex vivo, without the need for differentiation agents.

A combination of two compounds (FX03+VPA) may serve as a likely candidate to promote hair cell regeneration in vivo. This combination (formulation name FX-322) recently completed a Phase 1 safety trial in cochlear implant patients and a Phase 1/2 safety trial in patients with mild/moderate hearing loss. FX-322 was administered via intratympanic injection and showeed no adverse events in both studies.