Halofantrine protects photoreceptors in multiple models of retinal degeneration.

Inherited retinal degenerative diseases (IRDs), including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), cause progressive vision impairment due to photoreceptor degeneration. We previously demonstrated the protective effects of reserpine in models of CEP290-LCA and in the female Rhodopsin-P23H rat model of autosomal dominant RP. Given that reserpine is limited by side effects, we expanded our compound screen using retinal organoids from the rd16 mouse model of CEP290-LCA to include structurally diverse small molecules that may converge on proteostasis pathways. Follow-up evaluations in Rhodopsin-P23H rats, human CEP290-LCA retinal organoids, and rd10 mice (a model of PDE6B-RP) identified halofantrine as the most promising molecule, conferring strong protection to both rod and cone photoreceptors and demonstrating therapeutic potential across the divergent IRD models tested. Transcriptome analysis revealed a convergent molecular response to halofantrine across these models, primarily through upregulation of oxidative phosphorylation and ribosomal processes. Notably, halofantrine elicited significant improvements in retinal function, as assessed by electroretinography, despite pharmacokinetically limited and transient retinal exposure after subconjunctival injection in Rhodopsin-P23H rats. Our studies highlight the potential of halofantrine as a gene-independent therapy and suggest that it may be developed for ocular delivery via eye drops for the treatment of IRDs.