Aging-US: miR-106b suppresses pathological retinal angiogenesis
09-08-2021Aging-US published a Special Collection on Eye Disease which included "miR-106b suppresses pathological retinal angiogenesis" which reported that microRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression.
Here, the authors show that expression of the miR-106b-25 cluster is negatively regulated by the unfolded protein response pathway of protein kinase RNA-like ER kinase in a mouse model of neovascular AMD. They demonstrate that therapeutic delivery of miR-106b to the retina with lentiviral vectors protects against aberrant retinal angiogenesis in two distinct mouse models of pathological retinal neovascularization.
Dr. Przemyslaw Sapieha and Dr. Vincent De Guire said, "Age-related macular degeneration (AMD) is a common [1] and complex [2, 3] disease of aging and the leading cause of irreversible loss of sight in elderly people."
Early forms of AMD are characterized by subretinal lipoproteinaceous deposits, local attrition of photoreceptors and loss of visual sensitivity. Late forms of AMD are defined by geographic atrophy and/or pathologic choroidal neovascularization characterized by vascular sprouting from the choriocapillaris into the neural retina or subretinal space. Sustained reduction in retinal VEGF levels can lead to neurotoxicity and degeneration of RPE-choriocapillaris in mouse models. Importantly, assessment by fundus photography and fundus fluorescein angiography of patients on anti-VEGF therapy showed accelerated development of geographic atrophy. These findings justify the need for continued exploration of novel therapeutic interventions.
These findings justify the need for continued exploration of novel therapeutic interventions
Given that several inflammatory and growth factors in addition to VEGF are associated with the pathogenesis of NV AMD, a multi-targeted approach is warranted. The authors previously elucidated a specific miRNA signature in the vitreous and plasma of patients with NV AMD and observed a disease-associated increase in miR-146a and a decrease in miR-106b and miR-152. Interestingly, within this cohort, they found that both vitreous- and plasma-based miR-146a/miR-106b ratios had greater than 90% discriminatory power for classification of patients with NV AMD with an area under the receiver operating characteristic curve of 0,977 in vitreous humour and 0,915 in plasma, suggesting potential for a blood-based diagnostic.
Figure 6. Schematic of miR-106b impact on CNV in mouse laser burn model. (A) Bruch's membrane disruption following laser burn. (B) Intravitreal injection of LV.shGFP or LV.miR-106b. (C) PERK activation represses miR-106b expression and leads to pro-angiogenic factor overexpression, contributing to CNV formation. (D) Increased expression of miR-106b by LV leads to decreased CNV formation by targeting proangiogenic factor protein production. (CNV: choroidal neovascularization, LV: lentivirus).
The Sapieha/De Guire Research Team concluded in their Aging-US Research Output that there are efforts to devise therapeutics that simultaneously inhibit several factors involved in retinal vascular disease given the clinical success of compounds such as Aflibercept. miRNAs regulate translation of multiple genes and hence may be considered as multi-target inhibitors. Their potential to mitigate retinal disease will grow as comprehensive landscapes of miRNAs in health and disease are established. Preclinical studies are underway for mimics or inhibition of specific miRNAs.
Full Text - https://www.aging-us.com/article/202404/text
Correspondence to: Przemyslaw Sapieha email: mike.sapieha@umontreal.ca and Vincent De Guire email: vdeguire.hmr@ssss.gouv.qc.ca
Keywords: age related macular degeneration, miR-106b, PERK, choroidal neovascularization, angiogenesis
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