DKK1 inhibitor RM4404 restores corneal nerve regeneration and mechanosensory function in mouse injury models

Corneal nerve injuries, stemming from surgical procedures, trauma, or chemical exposure, frequently lead to significant and persistent loss of sensory function. This can result in debilitating corneal neuropathic pain and impaired vision, severely impacting quality of life. While corneal Schwann cells (cSCs) are known to provide crucial trophic support to axons, their specific role in promoting axonal regeneration after injury has remained largely uncharacterized. Current therapeutic approaches often fall short in achieving complete functional restoration, highlighting an urgent need for novel strategies that can actively promote intrinsic repair mechanisms. This study investigates Dickkopf-related protein 1 (DKK1), a candidate gene expressed in cSCs, as a potential therapeutic target to bridge this gap.

Researchers utilized Plp1-eGFP reporter mice to investigate cSCs and axonal responses in two distinct models of corneal nerve injury: the corneal micropocket injury (CMI) model, which induces focal stromal axonal severance, and acute exposure to nitrogen mustard (NM), causing blunt damage across the entire cornea. They developed a micellar formulation of RM4404, a small-molecule DKK1 inhibitor, for topical ocular application. This therapeutic agent was applied during the critical cSC regenerative phase, specifically from 7 to 14 days post-injury (dpi). Primary endpoints included quantitative assessment of cSC network recovery, axonal regeneration, and restoration of mechanosensory function, comparing treated groups to untreated controls.

After CMI, the cSC network rapidly declined over 7 dpi but recovered to uninjured control levels by 14 dpi, exhibiting sprouting at both injury and collateral areas. However, axons remained significantly lower than cSCs, leading to compromised mechanosensory functions. The NM injury model resulted in a sustained deficit in both cSCs and axons, with persistent mechanosensory loss observed through 14 dpi. Topical application of RM4404 during the cSC regenerative phase (7-14 dpi) significantly enhanced cSC repair in both injury paradigms. This improvement was coupled with a marked increase in axonal regeneration.

RM4404 treatment fully restored mechanosensory function in both the CMI and NM models, demonstrating a comprehensive functional recovery.