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Promises and challenges of miRNA therapeutics

2022; American Physical Society; Volume: 323; Issue: 6 Linguagem: Inglês

10.1152/ajprenal.00251.2022

1931-857X

Jianyin Long, Farhad R. Danesh,

RNA Interference and Gene Delivery

EditorialPromises and challenges of miRNA therapeuticsJianyin Long and Farhad R. DaneshJianyin LongSection of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas and Farhad R. DaneshSection of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TexasPublished Online:22 Nov 2022https://doi.org/10.1152/ajprenal.00251.2022This is the final version - click for previous versionMoreSectionsPDF (203 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Since the discovery of the first microRNA (miRNA) in Caenorhabditis elegans about three decades ago, a large body of evidence has clearly unraveled the regulatory roles of miRNAs in diverse biological processes of the cell (1, 2). miRNAs are single-stranded, endogenous, short (∼22 nt long) noncoding RNAs that serve as fine-tuning regulators of protein-encoding genes. miRNAs exert their regulatory role through silencing of their target genes via directing argonaute proteins to the complementary sequence in the 3′-untranslated region of their target mRNAs. Silencing of the target mRNAs is then achieved as miRNAs elicit miRNA-induced silencing complex-mediated degradation or cleavage of mRNAs (1, 2). Notably, a key feature of miRNA gene silencing is that a single miRNA can suppress multiple mRNAs, and, conversely, each target mRNA could also be regulated by multiple miRNAs. This characteristic gene targeting of miRNAs, while enhancing off-target effects of miRNA-based drugs, also represents an important pharmacological advantage since by targeting only one miRNA, it would be possible to manipulate a whole network of associated genes with regulatory roles in a specific cellular pathway.Considering the broad range of biological activities of miRNAs, it is no surprise that aberrant expression of miRNAs has been shown to be relevant to the molecular pathology of human diseases (3). Indeed, dysregulation of miRNAs has been shown to be associated, among other pathologies, with cancer, cardiovascular, and kidney diseases (4–6). Recognizing that abnormal miRNAs expression is frequently associated with human diseases has led to the notion that therapeutic targeting of miRNAs could be a powerful strategy for the treatment of a whole host of human diseases. This is of particular interest in view of recent successes toward the clinical application of RNA-based therapeutics in the era of the severe acute respiratory syndrome coronavirus 2 pandemic, which proved a turning point for the RNA-centric approaches as a viable and novel approach in several human pathologies.The use of miRNA-based therapeutics provides several clear potential advantages compared with small-molecule drug approaches that target single proteins. Most notably, miRNAs are endogenous and naturally occurring molecules in cells, and their targeting may inherently be advantageous with improved therapeutic effects compared with synthetic alternatives. Second, the ability of miRNAs to target multiple genes within a multitarget regulatory network suggests that their effects might lead to a broader response (7, 8). Finally, oligonucleotides can be chemically modified to enhance their pharmacokinetic-pharmacodynamic properties, an important advantage for their use as drugs. Accordingly, several strategies have emerged to manipulate levels of miRNAs using both miRNA mimics to restore miRNAs expression or miRNA inhibitors to deplete aberrantly expressed miRNAs (7, 8).miRNA mimics are chemically engineered double-stranded RNAs that could enhance the expression and function of endogenous miRNAs. Techniques to inhibit miRNA function, on the other hand, include the use of miRNA sponges, small-molecule inhibitors, and complementary oligonucleotides, such as antisense oligonucleotides (anti-miR ASOs; 7, 8). Anti-miR ASOs, possibly the most promising strategy, are engineered in the form of short single-stranded DNA molecules that bind to the complementary miRNA to form a stable DNA/RNA duplex, preventing the binding of miRNA to its target mRNAs. Anti-miR ASOs are commonly chemically modified at the 2′ carbon of the ribose as locked nucleic acids-ASOs for in vitro and in vivo use with improved extracellular and intracellular stability as well as enhanced resistance to nuclease degradation.miRNA-targeting therapies represent an area of intense interest and a promising pharmaceutical approach in kidney diseases, and numerous miRNAs have been reported to serve as promising candidates for a host of kidney diseases (4–6, 8). Indeed, miRNA inhibitors are currently being investigated against a variety of kidney diseases in clinical trials, including miR-21 ASO for the treatment of Alport disease under the name of Lademirsen and miR-17 ASO for the treatment of autosomal dominant polycystic kidney disease (4, 8).In an article recently published in the American Journal Physiology-Renal Physiology, Abdollahi et al. (9) reported a protective role for miR-379 deficiency in obesity-induced kidney injury using a high-fat diet (HFD) mouse model. Using miR-379 knockout (KO) mice generated by CRISPR/Cas9 editing (10), the authors compared renal phenotypes of HFD-fed miR-379 KO mice with wild-type (WT) mice. They found that in WT mice, HFD led to increased level of miR-379 and enhanced expression of the profibrotic transforming growth factor (TGF)-β1 gene, which resulted in lower expression levels of the endoplasmic reticulum (ER) degradation enhancer, mannosidase α-like 3 (Edem3) gene and Zeb2 gene, a negative regulator of TGF-β1. The authors observed that HFD-fed WT mice exhibited enhanced expression of several profibrotic genes, glomerular hypertrophy, and interstitial fibrosis in the kidneys, whereas these alterations were significantly attenuated in HFD-fed miR-379 KO mice. Notably, in cultured primary glomerular mesangial cells isolated from WT mice, targeting miR-379 with locked nucleic acid-modified ASOs (GapmeR) attenuated the profibrotic program induced by TGF-β1, including the induction of the profibrotic genes collagen type I-α2, collagen type IV-α1, and fibronectin-1 and repression of the miR-379 target Edem3 (9). These results suggest a miR-379/Edem3/Zeb2 signaling pathway in HFD-induced renal dysfunction. In a previous related study using a streptozotocin-induced diabetic kidney disease (DKD) model (10), the same group reported that genetic deletion of miR-379 could ameliorate key biochemical and morphometrical features of DKD, including albuminuria, glomerular hypertrophy, podocyte foot process effacement, and fibrosis as well as mitochondrial dysfunction, ER stress, and oxidative stress, mainly by enhancing adaptive mitophagy-mediated redox protein thioredoxin and mitochondrial fission-1, two key miR-379 targets (10). Collectively, these related reports provide compelling evidence on the signaling pathways underlying the pathophysiology of dysregulated miR-379 in kidney injuries (9, 10). miR-379 is the most upstream 5′-miRNA within the miR-379 megacluster of miRNAs hosted by the ER stress-regulated long noncondingRNA, lncMGC (10). Overall, the findings of this study suggest that ER stress induces the expression of miR-379 and TGF-β1, which, in turn, enhances the expression of miR-379 in a feedforward amplifying loop. Moreover, the in vitro data showing that miR-379 GapmeR can mitigate the TGF-β1-mediated profibrotic program in primary mesangial cells strongly suggest that miR-379 inhibition could be a promising therapeutic strategy for obesity-induced kidney disease and possibly DKD. Furthermore, this study, through an integrated approach with in vivo animal models and in vitro cell culture assays, provides a plethora of comprehensive data of the signaling pathways that improve our understanding of the complex regulatory role of miR-379. Together, findings in this study add a novel level of complexity to the pathobiology of miR-379 in obesity-induced kidney injury. However, one important gap of the study is the lack of an in vivo approach to target miR-379 in an animal model, to mimic genetic deletion of miR-379 in an HFD model. A careful examination of the specificity of miR-379 GapmeR should also be carried out to rule out off-target effects of miR-379 GapmeR on other miRNAs located on the miR-379 megacluster or on other genes located in the host lncMGC gene.Over the past decade, considerable effort has been made toward the transition of miRNA-based therapeutics into clinical use by minimizing their off-target effects. However, several key challenges have hampered the success of miRNA-based drugs for clinical use, including the design of targeting sequence to strengthen on-target specificity, engineering oligonucleotide modifications to enhance stability and cellular uptake, appropriate dosing for improving their efficiency and potency, cell/tissue-specific target delivery, avoiding the immunogenic response, and finally bearing biocompatible and biodegradable carrier materials (7, 8). Successful solutions to many of these challenges are ultimately anticipated. For instance, several sophisticated delivery methods are being explored such as liposome-based and nanoparticle (polymer)-based approaches to improved delivery of anti-miRs to specific target cells (7, 8). Furthermore, advanced strategies for miRNA therapeutics administration, such as implantable three-dimensional matrixes, inhalation schemes, and intake via food (8), are rapidly emerging.In conclusion, the study by Abdollahi et al. (9) advances our mechanistic understanding of the role of miR-379 in obesity-induced kidney disease. Further studies may be needed to demonstrate the value of targeting miR-379 in vivo.GRANTSThis work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants R01DK078900 (to F.R.D.) and R01DK091310 (to F.R.D.).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSJ.L. drafted manuscript; FRD edited and revised the manuscript; F.R.D. approved final version of manuscript.ACKNOWLEDGMENTSWe thank members of the Danesh laboratory, especially Dr. Benny Chang and Dr. Koki Mise, for their helpful comments and discussions regarding this manuscript.REFERENCES1. Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol 20: 21–37, 2019. doi:10.1038/s41580-018-0045-7. Crossref | PubMed | ISI | Google Scholar2. Bartel DP. Metazoan MicroRNAs. 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Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESCorrespondence: F. R. Danesh ([email protected]org). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Collections Related ArticlesFirst Author Spotlight 13 Dec 2022American Journal of Physiology-Renal Physiology More from this issue > Volume 323Issue 6December 2022Pages F673-F674 Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajprenal.00251.2022PubMed36264885History Received 29 September 2022 Accepted 17 October 2022 Published online 22 November 2022 Published in print 1 December 2022 KeywordsRNAmicroRNAskidneyobesitytherapeutics Metrics