Ophthalmology

OBJECTIVE: In the current study we aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date. In addition, we aimed to determine the effect of AMD-associated genetic variants on metabolite levels, and aimed to investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. DESIGN: Case-control assocation analysis of metabolomics data. SUBJECTS: 2,267 AMD cases and 4,266 controls from five European cohorts. METHODS: Metabolomics was performed using a high-throughput H-NMR metabolomics platform, which allows the quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d/C3 ratio) were investigated using linear regression. MAIN OUTCOME MEASURES: Metabolites associated with AMD RESULTS: We identified 60 metabolites that were significantly associated with AMD, including increased levels of large and extra-large HDL subclasses and decreased levels of VLDL, amino acids and citrate. Out of 52 AMD-associated genetic variants, seven variants were significantly associated with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, LIPC) with metabolites belonging to the large and extra-large HDL subclasses. In addition, 57 out of 60 metabolites were significantly associated with complement activation levels, and these associations were independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. CONCLUSIONS: Lipoprotein levels were associated with AMD-associated genetic variants, while decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways, and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD

Sirt1 activators induced neuroprotection of photoreceptors in rd10 mice

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.[Purpose]: It has been reported that Sirt1 nuclear expression decreases in the outer nuclear layer (ONL) of retinal degeneration 10 (rd10) mice at postnatal day 15 (P15), and this abnormal pattern is correlated with the beginning of photoreceptor degeneration. Sirt1 is a class III histone deacetylase, and over-expression of these proteins have shown neuroprotective effect in several experimental models of neurodegenerative diseases. However, it is still unknown whether Sirt1 modulation could induce neuroprotection of photoreceptors. We tested the hypothesis that subretinal injection of new Sirt1 activators would slow degeneration of photoreceptors using an experimental mouse model of autosomal recessive retinitis pigmentosa (RP).[Methods]: A library of resveratrol derivatives were newly synthesized in order to improve the solubility and bioavailability of this lead compound. The new optimized Sirt1 activators were tested for preclinical drug development. Rd10 mice (P13) were subretinal injected with 1 µL of vehicle, resveratrol or several new Sirt1 activators. Electroretinogram (ERG), fundus, and histological evaluation were performed 15 days after injections. Amplitude of a- and b-waves were quantified in ERG recordings, and the statistical analyses were calculated by one-way ANOVA and post hoc DMS. A p value < 0.05 was considered significant.[Results]: Fundus evaluation showed less amount of pigment patches in both JC19 and JC21 treated mouse retinas when compared with non-treated and vehicle treated rd10 mice (controls). In addition, the number of photoreceptors nuclei in the ONL and the immunostaining of rhodopsin were preserved in JC19 and JC21 treated mice. b-Wave amplitude in dark-adapted ERG (flash intensities of 0.2, 1, 3 and 10 cd x s/m2) significantly increased in JC21 treated mice when compared with controls. b-Wave amplitude also increased in resveratrol and JC19 treated groups but in a lesser extent. The amplitude of b-wave in dark-adapted ERG-10 was: non-treated=68.4 ± 6.7 µV, vehicle=79.3 ± 10.3 µV, resveratrol= 103.8 ± 12.1 µV (p < 0.05), JC19=110.3 ± 12.5 µV (p < 0.05), JC21= 129.8 ± 27.7 µV (p < 0.01). a-Wave amplitude also showed statistically significant differences in Sirt1 activators treated mice.[Conclusions]: Our results are consistent with our hypothesis that Sirt1 activators induce neuroprotection of photoreceptors in a mouse model of RP. Other retinal diseases could be potentially treated with these drugs.Peer reviewe

Modeling AIPL1-defect using iPS-derived retinal progenitors from a patient Leber Congenital Amaurosis

Póster presentado al Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), celebrado en Seattle, Washington (US) del 1 al 5 de mayo de 2016.Patient-derived cellular models can provide a specific tool to test new therapeutic approaches for retinal degenerative diseases. Mutations in AIPL1 are associated with Leber Congenital Amaurosis (LCA). Considering that AIPL1 protein is only expressed in photoreceptors we decided to establish a cellular model of AIPL1-LCA by differentiation of induced pluripotent stem cells (iPS) towards photoreceptor lineage.Grants: Junta de Andalucía; Fundación Progreso y Salud; Ministerio de Economía y Competitividad; Instituto de Salud Carlos III; EU H2020.Peer Reviewe

Sirt1 activators induced neuroprotection of photoreceptors in rd10 mice

Póster presentado al Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), celebrado en Seattle, Washington (US) del 1 al 5 de mayo de 2016.It has been report ed that Sirt1 nuclear expression decreases in the outer nuclear layer (ONL) of retinal degeneration 10 (rd10 ) mice at postnatal day 15 (P15), and this abnormal pattern is correlated with the beginning of photoreceptor degeneration. Sirt1 is a class III histone deacetylase, and over-­expression of these p roteins have shown neuroprotective effect in several experimental models of neurodegenerative diseases. However, it is still unknown whether Sirt1 modulation could induce neuroprotection of ph otoreceptors. We tested the hypothesis that subretinal injection of new Sirt1 activators would slow degeneration of photoreceptors using an experimental mouse model of autosomal recessive retinitis pigmentosa (RP).Support: ISCIII grants (Miguel Servet-­I, CP15/00071) and co-­funded by the European Regional Development Fund (ERDF). Andalusia Regional Government (FQM-­7316).Peer Reviewe

Prog Retin Eye Res

There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis