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5047.Full-Text.Pdf Th eJournal of Brief Reviews Immunology Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases Marisa E. Luck,* Stefan A. Muljo,† and Colm B. Collins* MicroRNAs (miRNAs) are endogenous oligoribonu- that bind to short, 6–8-bp complementary motifs on target cleotides with exciting therapeutic potential. Early stud- messenger RNAs (4), generally located within the 39 un- ies established a clear role for miRNAs in leukocyte translated region (UTR). The 6–8-bp complementary se- biology. The first miRNA-based therapy, miravirsen, quence at the 59 end of the miRNA is called the seed. Perfect is now in phase 2 clinical trials, making the reality of complementarity between the miRNA and its target triggers these therapies undeniable. The capacity for miRNAs RNA interference, cleavage mediated by the RNase H–like to fine-tune inflammatory signaling make them attractive domain of Ago2 (5, 6). However, in mammals, this has only treatment targets for immunological diseases. Nonetheless, been described for one target of miR-196 (7). In general, it is the degree of redundancy among miRNAs, coupled now believed that miRNAs promote deadenylation and with the promiscuity of miRNA binding sites in the tran- mRNA decay at steady-state in somatic mammalian cells (8). scriptome, require consideration when designing miRNA- Under specific circumstances, miRNAs were shown to inhibit directed interventions. Altered miRNA expression occurs initiation and/or elongation of protein translation (9). Recent evidence indicates that miRNAs repress protein translation by across a range of inflammatory conditions, including in- blocking assembly of the eukaryotic translation initiation flammatory bowel disease, arthritis, and diabetes. How- factor, eukaryotic initiation factor (eIF)4F. Specifically, ever, very few studies successfully treated murine models miRNAs form miRNA-induced silencing complexes with Ago of immunological diseases with miRNA-based approaches. proteins, which can either prevent association or actively While discussing recent studies targeting miRNAs to treat displace the RNA helicase, eIF4A, from the eIF4F complex, immunological conditions, we also reflect on the risks of thereby inhibiting the rate-limiting step in translation (10, miRNA targeting and showcase some newer delivery 11). Regardless of the mechanism, posttranscriptional control systems that may improve the pharmacological profile of gene expression by miRNAs provides a molecular rheostat of this class of therapeutics. The Journal of Immunol- to modulate specific genetic circuits, offering an additional ogy, 2015, 194: 5047–5052. layer to fine-tune the degree of protein synthesis. Current immunosuppressive therapies, such as steroids, icroRNAs (miRNAs) are short (∼22 nt) untrans- induce broad-spectrum suppression of immune responses, lated single-stranded endogenous RNAs. They which leads to increased susceptibility to infection. Targeting miRNAs may be of greater benefit for immunological diseases M are transcribed either individually or as part of by limiting their action to a gentle nudge to restore the complex a polycistronic transcriptional unit, and the resulting primary balance of our immune system between protecting and in- miRNA transcripts are processed in the nucleus by the nuclear juring the host. The feasibility of targeting miRNAs clinically RNase III–like enzyme Drosha (1). The excised hairpin has been given an enormous boost by the recent success of the intermediates or precursor miRNAs are exported from the pioneering miRNA-based therapeutic miravirsen (SPC-3649). nucleus and processed into mature miRNAs by the cyto- A locked nucleic acid (LNA)-based inhibitor of miR-122, plasmic RNase III–like enzyme Dicer (2) (Fig. 1). The clus- miravirsen is currently undergoing clinical trials for the tering of some miRNAs into transcriptional units suggests treatment of hepatitis C viral infections (12). The role of the that they may have coevolved to perform redundant, com- liver-specific miR-122 is somewhat unusual; instead of tar- plementary or sometimes antagonistic functions (3), a feature geting the 39 UTR and causing signal repression, it binds to that is discussed later. Once formed, mature miRNAs are the 59 UTR of hepatitis C virus RNA and promotes its rep- bound by argonaute (Ago) proteins and act as guide sequences lication. Miravirsen’s success thus far paves the way for a new *Mucosal Inflammation Program, Department of Pediatrics, University of Colorado tute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room School of Medicine, Aurora, CO 80045; and †Integrative Immunobiology Unit, Labo- 11N308, 10 Center Drive, MS1892, Bethesda, MD 20892 (S.A.M.) or Mucosal In- ratory of Immunology, National Institute of Allergy and Infectious Diseases, National flammation Program, Department of Pediatrics, University of Colorado School of Med- Institutes of Health, Bethesda, MD 20892 icine, 12700 East 9th Avenue, MS B146, Aurora, CO 80045 (C.B.C.). E-mail addresses: [email protected] (S.A.M.) or [email protected] (C.B.C.) Received for publication December 18, 2014. Accepted for publication March 19, 2015. Abbreviations used in this article: Ago, argonaute; EAE, experimental autoimmune This work is supported by the National Institutes of Health Intramural Research Pro- encephalomyelitis; eIF, eukaryotic initiation factor; LNA, locked nucleic acid; miRNA, gram of the National Institute of Allergy and Infectious Diseases (to S.A.M.), National microRNA; Treg, regulatory T cell; UTR, untranslated region. Institute of Diabetes and Digestive and Kidney Diseases Grant K01 DK099403-01 (to C.B.C.), and Crohn’s & Colitis Foundation of America Grant CDA 253596 (to C.B.C.). Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Address correspondence and reprint requests to Dr. Stefan A. Muljo or Dr. Colm B. Collins, Integrative Immunobiology Unit, Laboratory of Immunology, National Insti- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403146 Downloaded from http://classic.jimmunol.org by guest on September 30, 2021. Copyright 2015 Pageant Media Ltd. 5048 BRIEF REVIEWS: miRNAs AND HUMAN IMMUNOLOGICAL DISEASES plasticity. A similar phenomenon was observed in vivo during viralinfection(20),andmiRNAsmayprovideonemolecular mechanism that can control cell fate and ultimately shape im- mune responses. Cell-specific Dicer1 deletion also identified im- portant roles for miRNAs in the development and differentiation of B cells (21, 22), dendritic cells (23), and mast cells (24). Although these studies attest to the critical role of miRNAs in the maturation of the murine immune system, the global nature of the intervention—stopping production of all mature miRNA—makes it difficult to determine whether a single miRNA (or many miRNAs) may be responsible for the resulting phenotypes. Although there are miRNA target pre- diction algorithms, such as TargetScan (4) and PicTar (25), it is essential for the field to be able to identify and validate direct miRNA targets experimentally in a high-throughput fashion. Invaluable protocols, such as photoactivatable ribonucleoside- enhanced cross-linking and immunoprecipitation, although it FIGURE 1. MicroRNA biogenesis pathway. The miRNA gene is tran- requires metabolic labeling, and high-throughput sequencing scribed into primary miRNA within the nucleus and cleaved by the Drosha- Dgcr8 Microprocessor complex. Dicer then converts the resulting hairpin after UV–cross-linking and immunoprecipitation, which suf- intermediate, a precursor miRNA, to mature miRNA. This then binds to Ago fers from high background, have been developed (26, 27) for proteins, core components of RNA-induced silencing complexes, leading to target identification. However, a good Ab or affinity tag to mRNA deadenylation and decay, as well as inhibition of mRNA translation in enrich for Ago protein and large numbers of cells are required what is now thought to be an eIF4-dependent manner. for these approaches, which can limit the feasibility of experi- mental designs. For cross-linking and immunoprecipitation, it generation of miRNA-based therapeutics. Nevertheless, it is essential to have a negative control, such as an miRNA- must be noted that no approaches targeting miRNAs in the deficient control, to help to determine which Ago-binding immune system have advanced to clinical trials. Effective events are miRNA dependent (28). Moreover, the field needs targeting of hepatocytes by miravirsen does not guarantee the a better way to validate miRNA targets rather than highly ar- feasibility of targeting immune cells by any means. In fact, tificial luciferase reporter constructs in a heterologous trans- previous studies using unconjugated LNA-based miR-122 formed cell line. Although, it would be burdensome to mutate inhibitors demonstrated that significant accumulation of the endogenous miRNA binding sites, perhaps the field could LNA in hepatocytes occurred in an entirely passive manner propose agreeable alternate solutions. upon i.v. injection (13). Therefore, as we shall discuss in Nonetheless, the importance of miRNAs in immune cell greater detail, targeting of the immune system with miR- development makes them exciting targets for novel diagnostics based therapeutics offers significantly greater challenges. and therapeutic development. Later in this article, we discuss a number of the more critical hurdles associated with the suc- Indispensable role of miRNAs in immune cell development cessful targeting of specific
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