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

Acta Biomater

Institute of Biomedical Engineering, University of Toronto, 164 College Street, M5S 3G9 Toronto, Ontario, Canada; Donnelly Centre, University of Toronto, 160 College Street, M5S3E1 Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, 1 King's College Circle, M5S 1A8 Toronto, Ontario, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, M5S 3E5 Toronto, Ontario, Canada; Department of Chemistry, University of Toronto, 80 Saint George Street, M5S 3H6 Toronto, Ontario, Canada. Electronic address:

Published: April 2023

Retinitis pigmentosa (RP) is a group of genetic diseases that results in rod photoreceptor cell degeneration, 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 developed 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 controlled 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 dissociates 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. STATEMENT OF SIGNIFICANCE: Retinitis pigmentosa (RP) is the leading cause of inherited blindness in the world. Rod-derived cone viability factor (RdCVF), a novel protein paracrine factor, is effective in preclinical models of RP. To extend its therapeutic effects, we developed an affinity-controlled release strategy for the long form of RdCVF, RdCVFL. We expressed RdCVFL as a fusion protein with an Src homology 3 domain (SH3). We then utilized a hydrogel composed of hyaluronan and methylcellulose (HAMC) and modified it with SH3 binding peptides to investigate its release in vitro. Furthermore, we designed a mathematical model of the human eye to investigate delivery of the protein from the delivery vehicle. This work paves the way for future investigation of controlled release RdCVF.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2023.03.003DOI Listing

Publication Analysis

Top Keywords

affinity-controlled release
12
rod-derived cone
12
cone viability
12
viability factor
12
hamc-binding peptide
12
delivery vehicle
12
cone photoreceptor
8
retinitis pigmentosa
8
photoreceptor cell
8
blindness rod-derived
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!