Abstract
Dysregulation of iron metabolism is observed in animal models of retinitis pigmentosa (RP) and in patients with age-related macular degeneration (AMD), possibly contributing to oxidative damage of the retina. Transferrin (TF), an endogenous iron chelator, was proposed as a therapeutic candidate. Here, the efficacy of TF non-viral gene therapy based on the electrotransfection of pEYS611, a plasmid encoding human TF, into the ciliary muscle was evaluated in several rat models of retinal degeneration. pEYS611 administration allowed for the sustained intraocular production of TF for at least 3 and 6 months in rats and rabbits, respectively. In the photo-oxidative damage model, pEYS611 protected both retinal structure and function more efficiently than carnosic acid, a natural antioxidant, reduced microglial infiltration in the outer retina and preserved the integrity of the outer retinal barrier. pEYS611 also protected photoreceptors from N-methyl-N-nitrosourea-induced apoptosis. Finally, pEYS611 delayed structural and functional degeneration in the RCS rat model of RP while malondialdehyde (MDA) ocular content, a biomarker of oxidative stress, was decreased. The neuroprotective benefits of TF non-viral gene delivery in retinal degenerative disease models further validates iron overload as a therapeutic target and supports the continued development of pEY611 for treatment of RP and dry AMD.
Highlights
Iron is essential for retinal metabolism and visual cycle, but excessive ferrous iron (Fe2+) can generate reactive oxygen species (ROS) and consecutive oxidative damage to the cellular environment
Similar observations have been made following ciliary muscle electrotransfection of plasmids coding for other proteins, such as anti-TNF in animal models of uveitis [34,53], anti-VEGF in a rat model of choroidal neovascularization [54], and neurotrophic factors in rat models of retinal dystrophies [55], confirming that plasmid electrotransfection into the ciliary muscle is a valuable approach to deliver any therapeutic proteins to the retina
The light damage in rats is a well-established model of retinal degeneration inducing photoreceptor-specific cell death, breakdown of the blood–retina barrier, oxidative stress, inflammation, and subsequent loss of functional vision [56,57], recapitulating some of the hallmarks of dry age-related macular degeneration (AMD) and retinitis pigmentosa (RP) [58,59,60]
Summary
Iron is essential for retinal metabolism and visual cycle, but excessive ferrous iron (Fe2+) can generate reactive oxygen species (ROS) and consecutive oxidative damage to the cellular environment (reviewed in [1,2]). TF was highly potent to preserve photoreceptors in animal models of retinal degeneration induced by iron overload, light exposure, inherited genetic mutations, Pharmaceutics 2020, 12, 836 or retinal detachment [6,19,30] In these models, TF restored iron homeostasis, reduced oxidative stress, inflammation, and cell death, preserving photoreceptor cells and visual function [6,30]. We evaluated a non-viral gene therapy strategy that combines a plasmid coding for human TF (pEYS611), and an electrotransfection system to deliver DNA plasmids into the ciliary muscle, in order to sustainably produce apo-TF into the eye Such a technology was previously shown to efficiently allow the production of a variety of secreted proteins, including trophic factors, anti-TNF, or anti-VEGF [32,33,34,35,36]. These findings further validate iron overload as a therapeutic target for the treatment of retinal degeneration and pEYS611 as a valuable product to neutralize ocular iron excess
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