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Free Radic Biol Med. 2015 Dec;89:1105-21. doi: 10.1016/j.freeradbiomed.2015.08.018. Epub 2015 Oct 8.

Targeting iron-mediated retinal degeneration by local delivery of transferrin.

Author information

1
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.
2
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.
3
INSERM, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
4
INSERM, U1138, CICC, Université René Descartes Sorbonne Paris Cité, Université Pierre et Marie Curie Paris, Centre de Recherche des Cordeliers, Paris, France.
5
INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Department of Ophthalmology, Purpan Hospital, Toulouse, France.
6
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.

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.

KEYWORDS:

Inflammation; Iron; Neurodegenerative diseases; Neuroprotection; Oxidative stress; Transferrin

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