An Eye on Age-Related Macular Degeneration: The Role of MicroRNAs in Disease Pathology

Abstract

Age-related macular degeneration (AMD) is the primary cause of blindness in developed countries, and is the third leading cause worldwide. Emerging evidence suggests that beside environmental and genetic factors, epigenetic mechanisms, such as microRNA (miRNA) regulation of gene expression, are relevant to AMD providing an exciting new avenue for research and therapy. MiRNAs are short, non-coding RNAs thought to be imperative for coping with cellular stress. Numerous studies have analyzed miRNA dysregulation in AMD patients, although with varying outcomes. Four studies which profiled dysregulated circulating miRNAs in AMD yielded unique sets, and there is only minimal overlap in ocular miRNA profiling of AMD. Mouse models of AMD, including oxygen-induced retinopathy and laser-induced choroidal neovascularization, showed similarities to some extent with miRNA patterns in AMD. For example, miR-146a is an extensively researched miRNA thought to modulate inflammation, and was found to be upregulated in AMD mice and cellular systems, but also in human AMD retinae and vitreous humor. Similarly, mir-17, miR-125b and miR-155 were dysregulated in multiple AMD mouse models as well as in human AMD plasma or retinae. These miRNAs are thought to regulate angiogenesis, apoptosis, phagocytosis, and inflammation. A promising avenue of research is the modulation of such miRNAs, as the phenotype of AMD mice could be ameliorated with antagomirs or miRNA-mimic treatment. However, before meaningful strides can be made to develop miRNAs as a diagnostic or therapeutic tool, reproducible miRNA profiles need to be established for the various clinical outcomes of AMD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40291-016-0234-z) contains supplementary material, which is available to authorized users.

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

“…Because miR-155 is associated to blood brain barrier dysfunction (Lopez-Ramirez et al, 2014), the up-regulation of miR-155 in retina of rats injected with Aβ oligomers might also influence the integrity of blood retinal barrier (BRB). MiR-155 and its angiogenic target gene CCN1 were found to alter vascular and neovascular growth in mice retina (Berber et al, 2017). Increased expression of miR-155 induced formation of neovascular tufts that growth abnormally in vitreous with concomitant retinal microglial activation (Yan et al, 2015); thus, up-regulation of miR-155 in retina of Aβ injected rats might be the triggering factor of retinal inflammation and pro-angiogenic events.…”

“…Therefore, identification and validation of serum, minimally-invasive, biomarkers of AMD are still challenging. In this perspective, differential expression of miRNAs in serum or plasma represents a potential approach to identify novel biomarkers and pharmacological targets of AMD as suggested by Berber et al in their compelling review (Berber et al, 2017). MiRNAs are short, approximately 22-mer, non-coding RNA molecules bearing important regulatory functions, such as post-transcriptional regulation of gene expression (Bartel, 2004).…”

“…Extracellular miRNAs are stable due to association to cell-derived nanovesicles (e.g., exosomes), RNA-binding proteins (e.g., Argonaute 2) or high density lipoproteins HDL (Creemers et al, 2012). Recently, miRNAs were analyzed in vitreous and plasma of exudative AMD patients, by means of non-biased miRNA arrays and validation with qPCR; miRNA-146a was found to be significantly up-regulated both in vitreous and plasma of AMD patients (Ménard et al, 2016; Berber et al, 2017). Interestingly, miRNA-146a is found also down-regulated in cerebrospinal fluid (CSF) of AD patients (Kiko et al, 2014; Müller et al, 2014; Denk et al, 2015).…”

Expression of VEGFA‐regulating miRNAs and mortality in wet AMD

“…A recent study has identified as many as 416 miRNAs which are expressed in RPE and choroid . Targeting these miRNAs in order to modulate their expression seems to be a promising strategy in AMD treatment as supported by experiments conducted in animal models of AMD …”

miR‐539‐5p inhibits experimental choroidal neovascularization by targeting CXCR7

“…MicroRNAs (miRNAs) are a class of small, noncoding RNAs that negatively regulate gene expression posttranscriptionally by partial or full complementary matching with the 39-UTR of target mRNAs (14). Recent studies in animals and humans have revealed important functions of miRNAs in the development and progression of wet AMD (15)(16)(17). Thus far, several miRNAs with proangiogenic (miR- 23, -27, and -155) or antiangiogenic (miR-31, -150, -24, -29, and -93) functions have been identified by using the laser-induced CNV murine model, a wellestablished model that closely mimics the pathogenesis of AMD in humans (18)(19)(20)(21)(22)(23)(24); however, it remains unclear whether other miRNAs, especially those that target to CXCR7, are also involved in the process of angiogenesis in CNV.…”