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Light-induced Nrf2-/- mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel.

ABSTRACT: Elevated oxidative stress and associated reactive oxygen species (ROS) accumulation are hallmarks in the induction and progression of age-related macular degeneration (AMD). By exposing nuclear factor erythroid 2-related factor (Nrf2) knockout (Nrf2-/-) mice to mild white light, we were able to generate a new dry-AMD like murine model to the study. This animal model developed phenotypes of photoreceptor degeneration, retinal function impairment, ROS accumulation, and inflammation reaction in a relatively shorter time. In the treatment of this animal model we utilized an antioxidative and water soluble nanoparticle known as glycol chitosan coated cerium oxide nanoparticles (GCCNP). The delivery of GCCNP protected retina against progressive retinal oxidative damage. Further combination of GCCNP with alginate-gelatin based injectable hydrogel provided synergistic antioxidant effects and achieved a more rapid recovery of the retinal pigment epithelium and photoreceptor cells. This combined treatment technique has the potential to translate into a clinical intervention for the treatment of AMD.

SUBMITTER: Wang K

PROVIDER: S-EPMC6787253 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Light-induced Nrf2<sup>-/-</sup> mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel.

Wang Kai K Zheng Min M Lester Kaitlyn Lee KL Han Zongchao Z

Scientific reports 20191010 1

Elevated oxidative stress and associated reactive oxygen species (ROS) accumulation are hallmarks in the induction and progression of age-related macular degeneration (AMD). By exposing nuclear factor erythroid 2-related factor (Nrf2) knockout (Nrf2<sup>-/-</sup>) mice to mild white light, we were able to generate a new dry-AMD like murine model to the study. This animal model developed phenotypes of photoreceptor degeneration, retinal function impairment, ROS accumulation, and inflammation reac ...[more]

PMID: 31601909

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Project description:PurposeTo evaluate the therapeutic potential and safety of intravitreal injections of bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with atrophic age-related macular degeneration (AMD).MethodsTen patients with atrophic AMD and best-corrected visual acuity (BCVA) in the worse-seeing eye of ≤20/100 were enrolled in this study. The bone marrow from all patients was aspirated and processed for mononuclear cell separation. A 0.1 mL suspension of BMMF CD34+ cells was injected into the vitreous cavity of the worse-seeing eye. Patients were evaluated at Baseline and 1,3,6,9 and 12 months after injection. Ophthalmic evaluation included BCVA measurement, microperimetry, infrared imaging, fundus autofluorescence and SD-optical coherence tomography at all study visits. Fluorescein angiography was performed at Baseline and at 6 and 12 months after intravitreal therapy.ResultsAll patients completed the 6-month follow-up, and six completed the 12-month follow-up. Prior to the injection, mean BCVA was 1.18 logMAR (20/320-1), ranging from 20/125 to 20/640-2, and improved significantly at every follow-up visit, including the 12-month one, when BCVA was 1.0 logMAR (20/200) (P<0.05). Mean sensitivity threshold also improved significantly at 6, 9 and 12 months after treatment (P<0.05). Considering the area of atrophy identified by fundus autofluorescence, significant mean BCVA and mean sensitivity threshold improvement were observed in patients with the smallest areas of atrophy. Fluorescein angiography did not identify choroidal new vessels or tumor growth.ConclusionThe use of intravitreal BMMF injections in patients with AMD is safe and is associated with significant improvement in BCVA and macular sensitivity threshold. Patients with small areas of atrophy have a better response. The paracrine effect of CD34+ cells may explain the functional improvement observed; however, larger series of patients are necessary to confirm these preliminary findings.

Project description:PurposeLoss of photoreceptors in atrophic age-related macular degeneration results in severe visual impairment, although some peripheral vision is retained. To restore central vision without compromising the residual peripheral field, we developed a wireless photovoltaic retinal implant (PRIMA; Pixium Vision, Paris, France) in which pixels convert images projected from video glasses using near-infrared light into electric current to stimulate the nearby inner retinal neurons.DesignWe carried out a first-in-human clinical trial to test the safety and efficacy of the prosthesis in patients with geographic atrophy (ClinicalTrials.gov identifier, NCT03333954).ParticipantsFive patients with geographic atrophy zone of at least 3 optic disc diameters, no foveal light perception, and best-corrected visual acuity of 20/400 to 20/1000 in the worse-seeing study eye.MethodsThe 2-mm wide, 30-μm thick chip, containing 378 pixels (each 100 μm in diameter), was implanted subretinally in the area of atrophy (absolute scotoma).Main outcome measuresAnatomic outcomes were assessed with fundus photography and OCT for up to 12 months of follow-up. Prosthetic vision was assessed by mapping light perception, bar orientation, letter recognition, and Landolt C acuity.ResultsIn all patients, the prosthesis was implanted successfully under the macula, although in 2 patients, it was implanted in unintended locations: within the choroid and off center by 2 mm. All 5 patients could perceive white-yellow prosthetic visual patterns with adjustable brightness in the previous scotomata. The 3 with optimal placement of the implant demonstrated prosthetic acuity of 20/460 to 20/550, and the patient with the off-center implant demonstrated 20/800 acuity. Residual natural acuity did not decrease after implantation in any patient.ConclusionsImplantation of the PRIMA did not decrease the residual natural acuity, and it restored visual sensitivity in the former scotoma in each of the 5 patients. In 3 patients with the proper placement of the chip, prosthetic visual acuity was only 10% to 30% less than the level expected from the pixel pitch (20/420). Therefore, the use of optical or electronic magnification in the glasses as well as smaller pixels in future implants may improve visual acuity even further.

Project description:Atrophic age-related macular degeneration (AMD) is the most common form of AMD accounting for 90% of patients. During atrophic AMD the waste/exchange pathway between the blood supply (choroid) and the retinal pigment epithelium (RPE) is compromised. This results in atrophy and death of the RPE cells and subsequently the photoreceptors leading to central blindness. Although the mechanisms behind AMD are unknown, the growth of fatty deposits known as drusen, have been shown to play a role in the disease. There is currently no treatment or cure for atrophic AMD. Much research focuses on developing a synthetic substrate in order to transplant healthy cells to the native Bruch's membrane (BM), however, the diseased native BM and related structures still leave potential for transplanted cells to succumb to disease. In this proof-of-concept work we electrospun poly(ethylene terephthalate) (PET) to fabricate a nanofibrous cytocompatible synthetic BM. The apical surface of the membrane was cultured with ARPE-19 cells and the underside was decorated with poly(lactic acid-co-glycolic acid) (PLGA) or poly(glycolic acid) (PGA) degradable nanoparticles by electrospraying. The membrane exhibited hydrophilicity, high tensile strength and structurally resembled the native BM. ARPE-19 cells were able to form a monolayer on the surface of the membrane and no cell invasion into the membrane was seen. The presence of both PLGA and PGA nanoparticles increased ARPE-19 cell metabolism but had no effect on cell viability. There was a decrease in pH of ARPE-19 cell culture media 7 days following culturing with the PLGA nanoparticles but this change was eliminated by 2 weeks; PGA nanoparticles had no effect on cell culture media pH. The fluorescent dye FITC was encapsulated into nanoparticles and showed sustained release from PLGA nanoparticles for 2 weeks and PGA nanoparticles for 1 day. Future work will focus on encapsulating biologically active moieties to target drusen. This could allow this novel bioactive substrate to be a potential treatment for atrophic AMD that would function two-fold: deliver the required monolayer of healthy RPE cells to the macula on a synthetic BM and remove diseased structures within the retina, restoring the waste/exchange pathway and preventing vision loss.

Dataset Information

Light-induced Nrf2-/- mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel.

Publications

Light-induced Nrf2<sup>-/-</sup> mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel.

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