title: Targeting iron-mediated retinal degeneration by local delivery of transferrin.
abstract: Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration. After intravitreal injection, Tf spread rapidly within the retina and accumulated in photoreceptors and retinal pigment epithelium, before reaching the blood circulation. Tf injected in the vitreous prior and, to a lesser extent, after light-induced retinal degeneration, efficiently protected the retina histology and function. We found an association between Tf treatment and the modulation of iron homeostasis resulting in a decrease of iron content and oxidative stress marker. The immunomodulation function of Tf could be seen through a reduction in macrophage/microglial activation as well as modulated inflammation responses. In a mouse model of hemochromatosis, Tf had the capacity to clear abnormal iron accumulation from retinas. And in the slow P23H rat model of retinal degeneration, a sustained release of Tf in the vitreous via non-viral gene therapy efficently slowed-down the photoreceptors death and preserved their function. These results clearly demonstrate the synergistic neuroprotective roles of Tf against retinal degeneration and allow identify Tf as an innovative and not toxic therapy for retinal diseases associated with oxidative stress.
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France. Electronic address: emilie.picard@crc.jussieu.fr.
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Le Rouzic
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Oudar
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Berdugo
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Sanharawi
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andrieu-Soler
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Jonet
authors.affiliation: INSERM, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Latour
authors.affiliation: INSERM, U1138, CICC, Université René Descartes Sorbonne Paris Cité, Université Pierre et Marie Curie Paris, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Klein
authors.affiliation: INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Department of Ophthalmology, Purpan Hospital, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Galiacy
authors.affiliation: INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Department of Ophthalmology, Purpan Hospital, Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Malecaze
authors.affiliation: INSERM, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Coppin
authors.affiliation: INSERM, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Jeanny
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Courtois
authors.affiliation: INSERM, UMRS 1138, team Behar-Cohen, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Université René Descartes, Centre de Recherche des Cordeliers UMRS 1138, Paris, France; Jules Gonin Ophthalmic Hospital, Lausanne, Switzerland.
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D007501:Iron / Q000633:toxicity*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014168:Transferrin / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D014168:Transferrin; D007501:Iron
keywords: Inflammation; Iron; Neurodegenerative diseases; Neuroprotection; Oxidative stress; Transferrin