Successful proof-of-concept for topical delivery of novel peptide ALM201 with potential utility for treating neovascular eye disorders

PURPOSE: To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathologic vascularization. DESIGN: Experimental study in mouse, rat, and rabbit animal models. PARTICIPANTS: Ten-week-old Lister Hooded male rats, 8-week-old Brown Norway male rats, 9-day-old C57BL/6J mice, and 12-month-old New Zealand male rabbits. METHODS: Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging after topical ALM201 application to rabbit eyes. A mouse choroidal sprouting assay, with aflibercept as positive control, was used to evaluate choroidal neovascularization (CNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed using a rat laser CNV model of neovascular age-related macular degeneration. MAIN OUTCOME MEASURES: Clinical scoring and histologic analysis of vascularized corneas, sprouting area, lesion size, and vessel leakiness in posterior segments. RESULTS: Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (P = 0.0065) and vessel distance to suture (P = 0.021) compared with vehicle control (phosphate-buffered saline [PBS]). Infiltration of inflammatory cells into the corneal stroma also was reduced significantly compared with PBS (724.5 ± 122 cells/mm(2) vs. 1837 ± 195.9 cells/mm(2), respectively; P = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in anterior and posterior ocular segments 1 hour after topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared with PBS treatment (44.5 ± 14.31 pixels vs. 120.9 ± 33.37 pixels, respectively; P = 0.04) and was not inferior to aflibercept (65.63 ± 11.86 pixels; P = 0.7459). Furthermore, topical ALM201 significantly improved vessel leakiness (leakage scores: 2.1 ± 0.7 vs. 2.9 ± 0.1; P = 0.0274) and lesion size (144,729 ± 33,239 μm(3) vs. 187,923 ± 28,575 μm(3); P = 0.03) in the rat laser CNV model when compared with topical PBS vehicle. CONCLUSIONS: ALM201 is a promising novel molecule with anti-inflammatory and antivascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered therapeutic agent for treating inflammation and pathologic vascularization in the anterior and posterior segments of the eye

Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications

The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed

Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ—A Pilot Study

Inflammation is key to the pathogenesis of diabetic retinopathy (DR). This prospective study investigated alterations in inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) in 41 people with type 1 diabetes (T1D), sub-grouped into mild non-proliferative DR (mNPDR; n = 13) and active and inactive (each n = 14) PDR. Age/gender-matched healthy controls (n = 13) were included. PBMCs were isolated from blood samples. Intracellular cytokine expression by PBMCs after 16-h stimulation (either E. coli lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate plus ionomycin, D-glucose or D-mannitol) were assessed by flow cytometry. Cytokine production in plasma, non-stimulated and LPS-stimulated PBMC supernatant was also assessed. Increased BMC IL-10 secretion and reduced expression of IL-6 and IFN-γ in CD3+ cells were observed in mNPDR. Reduced IL-6 and IL-10 secretion, and higher levels of intracellular IL-6 expression, especially in CD11b+ PBMCs, was detected in aPDR; levels were positively correlated with DR duration. Patients with T1D demonstrated increased intracellular expression of IL-17A in myeloid cells and reduced IFN-γ expression in CD3+ cells. Plasma levels of IL-1R1 were increased in mNPDR compared with controls. Results suggest that elevated PBMC-released IL-10, IL-6, in particular myeloid-produced IL-17A, may be involved in early stages of DR. IL-6-producing myeloid cells may play a role in PDR development

Peripheral blood mononuclear cells from patients with type 1 diabetes and diabetic retinopathy produce higher levels of IL-17A, IL-10 and IL-6 and lower levels of IFN-γ-a pilot study

Inflammation is key to the pathogenesis of diabetic retinopathy (DR). This prospective study investigated alterations in inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) in 41 people with type 1 diabetes (T1D), sub-grouped into mild non-proliferative DR (mNPDR; n = 13) and active and inactive (each n = 14) PDR. Age/gender-matched healthy controls (n = 13) were included. PBMCs were isolated from blood samples. Intracellular cytokine expression by PBMCs after 16-h stimulation (either E. coli lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate plus ionomycin, D-glucose or D-mannitol) were assessed by flow cytometry. Cytokine production in plasma, non-stimulated and LPS-stimulated PBMC supernatant was also assessed. Increased BMC IL-10 secretion and reduced expression of IL-6 and IFN-γ in CD3+ cells were observed in mNPDR. Reduced IL-6 and IL-10 secretion, and higher levels of intracellular IL-6 expression, especially in CD11b+ PBMCs, was detected in aPDR; levels were positively correlated with DR duration. Patients with T1D demonstrated increased intracellular expression of IL-17A in myeloid cells and reduced IFN-γ expression in CD3+ cells. Plasma levels of IL-1R1 were increased in mNPDR compared with controls. Results suggest that elevated PBMC-released IL-10, IL-6, in particular myeloid-produced IL-17A, may be involved in early stages of DR. IL-6-producing myeloid cells may play a role in PDR development