Halofantrine protects photoreceptors in multiple models of retinal degeneration [rd10]

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 on 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.