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

Autor: Teal CJ; 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., Ho MT; 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., Huo L; 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., Harada H; Donald K. Johnson Research Institute, Krembil Research Institute, Krembil Discovery Tower, Toronto, Ontario, Canada., Bahlmann LC; 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., Léveillard T; Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France., Monnier PP; Donald K. Johnson Research Institute, Krembil Research Institute, Krembil Discovery Tower, Toronto, Ontario, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Ramachandran A; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, M5S 3E5 Toronto, Ontario, Canada., Shoichet MS; 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: molly.shoichet@utoronto.ca.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2023 Apr 15; Vol. 161, pp. 37-49. Date of Electronic Publication: 2023 Mar 08.
DOI: 10.1016/j.actbio.2023.03.003
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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