Affinity-controlled release of rod-derived cone viability factor enhances cone photoreceptor survival

Retinitis pigmentosa (RP) is a group of genetic diseases that results in rod photoreceptor cell degenera-tion, which subsequently leads to cone photoreceptor cell death, impaired vision and eventual blindness. Rod-derived cone viability factor (RdCVF) is a protein which has two isoforms: a short form (RdCVF) and a long form (RdCVFL) which act on cone photoreceptors in the retina. RdCVFL protects photoreceptors by reducing hyperoxia in the retina; however, sustained delivery of RdCVFL remains challenging. We devel-oped an affinity-controlled release strategy for RdCVFL. An injectable physical blend of hyaluronan and methylcellulose (HAMC) was covalently modified with a peptide binding partner of the Src homology 3 (SH3) domain. This domain was expressed as a fusion protein with RdCVFL, thereby enabling its con-trolled release from HAMC-binding peptide. Sustained release of RdCVFL was demonstrated for the first time as RdCVFL-SH3 from HAMC-binding peptide for 7 d in vitro . To assess bioactivity, chick retinal disso-ciates were harvested and treated with the affinity-released recombinant protein from the HAMC-binding peptide vehicle. After 6 d in culture, cone cell viability was greater when cultured with released RdCVFL-SH3 relative to controls. We utilized computational fluid dynamics to model release of RdCVFL-SH3 from our delivery vehicle in the vitreous of the human eye. We demonstrate that our delivery vehicle can prolong the bioavailability of RdCVFL-SH3 in the retina, potentially enhancing its therapeutic effects. Our affinity-based system constitutes a versatile delivery platform for ultimate intraocular injection in the treatment of retinal degenerative diseases.

Automated summary

Retinitis pigmentosa (RP) is a genetic disease that leads to degeneration of rod photoreceptor cells, resulting in impaired vision and blindness. We developed an affinity-controlled release strategy using a modified blend of hyaluronan and methylcellulose (HAMC) to deliver the protein RdCVFL to the retina. Our system demonstrated sustained release of RdCVFL and enhanced cone cell viability, potentially improving the treatment of retinal degenerative diseases.