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Aimee Jackson

The Therapeutic Potential of microRNA Modulation

Abstract: microRNAs are endogenous small non-coding RNAs that regulate gene expression by interfering with translation or stability of target transcripts. The importance and varied functions of microRNAs are illustrated by the diverse phenotypes, including disease, that arise when microRNAs are mutated or improperly expressed. The association of microRNA dysfunction with disease phenotypes has given rise to the idea that selective modulation of microRNAs could alter the course of disease. With the recent demonstration that inhibition of miR-122 reduces viral load in HCV-infected chimpanzees, microRNA modulators are no longer merely theoretical, but have become strong candidate therapeutics. Here we review the evidence for microRNA dysfunction in human disease, as well as recent examples of microRNA modulation that provided therapeutic benefit.

The microRNAs

microRNAs were first identified in C. elegans as small RNAs that control key developmental transitions (Reinhart et al., 2000; Lee and Ambros, 2001). microRNAs have now been identified in species from worms to humans as endogenous ~22 nucleotide non-coding RNAs that regulate expression of target genes through sequence-specific hybridization to the 3′ untranslated region (UTR) of target messenger RNAs. Many microRNAs are conserved across multiple species, indicating their evolutionary importance as modulators of biological pathways. microRNAs may regulate gene networks or pathways to control biological functions, playing important roles in differentiation, development, and physiology. microRNAs mediate gene expression through mRNA degradation or translational arrest (Bartel, 2009; Carthew and Sontheimer, 2009). microRNAs bind multiple target mRNAs with partial complementarity, mostly involving residues 1-8 (the seed sequence) of the microRNA guide strand (Lai, 2002). Since microRNAs do not require perfect complementarity for target recognition, a single microRNA is able to regulate multiple, perhaps hundreds of, messenger RNAs (Lim et al., 2005; Baek et al., 2008; Selbach et al., 2008). It is estimated that microRNAs as a class regulate the expression of 60% of genes in the genome (Friedman et al., 2009).

The Targets

Since a single microRNA can regulate hundreds of targets, the biological functions of microRNAs are not always obvious from an examination of their targets. The identification of biological targets of microRNAs can be aided by the use of predictive computer algorithms, but these algorithms predict only ~50% of the regulated targets detected by microarrays and other global detection techniques (Baek et al., 2008). microRNA target regulation is best measured using global mRNA expression methods, such as microarray, coupled with statistical techniques that can measure small changes in many genes to identify the significantly regulated, seed-matched targets. Some microRNAs target sets of transcripts that function in the same or related pathways, which can provide insight into the biological roles of these microRNAs (Stark et al., 2003; Grun et al., 2005; Lewis et al., 2005; Linsley et al., 2007). However, the repertoires of transcripts targeted by many microRNAs are not statistically enriched for specific biological functions or processes, or enrichment might involve only a minority of the targets. It can therefore be difficult to determine which target(s) are responsible for microRNA phenotypes.

microRNAs could impact a given phenotype through regulation of a single key target, or through concomitant regulation of a subset of targets. In some instances a phenotype can be explained by partial suppression of a single target, as illustrated by the ability of miR-150 to control lymphocyte development by regulating the expression of the seed-matched target c-Myb (Xiao et al., 2007). For other microRNAs the story is more complex, with the phenotype being controlled by the coordinated suppression of multiple targets (Linsley et al., 2007; Georges et al., 2008; Valastyan et al., 2009). microRNAs regulate each individual mRNA only modestly (~30-50% down-regulation), but the coordinated regulation of multiple targets enables microRNAs to orchestrate phenotypic changes. When applied to a therapeutic context, this ability to modulate the expression of a network of genes is reminiscent of combination therapy.

microRNA Disruption Yields Diverse Phenotypes

Initial data suggested that finding phenotypes for microRNA disruption would be difficult (Miska et al., 2007). However, examination under multiple conditions has revealed diverse phenotypes arising from microRNA disruption. microRNAs have critical functions in numerous biological processes. As an example, deletion of several different microRNAs results in cardiovascular defects, implicating them as key regulators of cardiovascular development and repair. Homozygous deletion of miR-1 results in cardiomyocyte hyperplasia and cardiac electrophysiology defects (Zhao et al., 2007). Mice with miR-208 loss-of-function mutations display defective cardiac remodeling after stress (van Rooij et al., 2007). Targeted deletion of miR-126 leads to defective vascular integrity and hemorrhaging as a result of defective endothelial cell proliferation, migration, and angiogenesis (Kuhnert et al., 2008; Wang et al., 2008). Deletion of both alleles of miR-133 causes lethal ventricular-septal defects in ~50% of neonates, and those mice that survive to adulthood suffer from dilated cardiomyopathy and heart failure (Liu et al., 2008).

microRNAs have also been shown to be important regulators of the immune system. Mice with deletion of miR-155 are immunodeficient, with abnormal B cells, T cells, and dendritic cells (Rodriguez et al., 2007; Thai et al., 2007) and defective IgG1 class switching (Vigorito et al., 2007). miR-150 deficiency leads to expansion of mature B cells and enhanced humoral immune response, revealing a role for miR-150 in lymphocyte development (Xiao et al., 2007). miR-223 also functions in the development of immune cells, regulating development of myeloid cells. Mice lacking miR-223 have elevated levels of granulocytes in the bone marrow and peripheral blood. miR-223-deficient granulocytes have a hypermature morphology, are hyperreactive to activating stimuli, and display enhanced fungicidal activity (Johnnidis et al., 2008).

microRNA loss-of-function studies have also revealed roles for microRNAs in cancer (Klein et al., 2010), regulation of blood glucose levels (Poy et al., 2009), maintaining blood pressure (Xin et al., 2009), and regeneration of neuromuscular synapses after nerve injury (Williams et al., 2009). Thus, evidence is accumulating that the precise regulation of gene expression patterns by microRNAs is important for vertebrate development and function.

Altered microRNAs in Human Disease

Since microRNAs have critical functions in numerous biological processes, altered expression or function of microRNAs might accompany human disease. microRNA expression analysis of human cancer samples revealed altered microRNA expression patterns capable of classifying tumors according to type and tissue of origin (Lu et al., 2005; Volinia et al., 2006). Interestingly, microRNA expression profiles successfully classified poorly differentiated tumors, while mRNA expression profiles were highly inaccurate for the same samples. The implication from these data is that, unlike mRNA expression, a relatively small number of microRNAs can successfully classify, and therefore potentially diagnose, human cancers. Dysregulation of miR-21, miR-17-5p, and miR-191 was observed in tumors of multiple different origins, suggesting that altered expression of these microRNAs deregulates a fundamental pathway(s) common to many cancers. In addition to cancer, alterations in microRNA expression have been observed in other disease settings, strengthening the association between microRNA expression and disease.

Altered function of microRNAs might also be directly causative in human disease. In one study, mutations in the 3′ UTR of a candidate disease gene that disrupt microRNA binding sites were associated with Tourette’s syndrome. A subset of patients displayed a single base mutation in the miR-189 target site within the 3′ UTR of the gene encoding SLITRK1, previously implicated in Tourette’s syndrome (Abelson et al., 2005). This gene variant was absent from 4,296 control chromosomes, suggesting significant association with the disease. The mutation replaces a G:U wobble base pair with an A:U Watson-Crick pair at position 9 in the microRNA binding domain of SLITRK1, and leads to increased repression of the target relative to the wild type 3′ UTR sequence. When expressed in mice, the mutated human SLITRK1 produced shorter dendrites in cortical pyramidal neurons compared to the wild type SLITRK1, suggesting that the frameshift mutation in the miR-189 binding site leads to loss of function of SLITRK1. Therefore, altered interaction of miR-189 with the target transcript SLITRK1 might contribute to Tourette’s syndrome in patients carrying the mutated target site.

Loss of function of miR-96, a microRNA expressed in hair cells of the inner ear (Weston et al., 2006), has a potentially causative role in hearing loss (Mencia et al., 2009). Mapping of an autosomal dominant deafness locus in a Spanish family identified a candidate cluster containing three genes encoding microRNAs (MIRN96, MIRN182, MIRN183). Sequencing analysis revealed a G-to-A transition at position 13 of the allele, corresponding to position 5 of the seed region of the mature miR-96 microRNA. This point mutation segregated with the hearing loss in this family, but was not detected in 462 normal-hearing Spanish controls. These findings implicate the miR-96 seed mutation as the cause of hearing loss in this family. In a second family, a C-to-A transversion at position 14 of the allele, corresponding to position 6 of the mature miR-96 microRNA segregated with hearing loss and was absent from controls. Positions 5 and 6 of miR-96 are highly evolutionarily conserved. When expressed in HeLa cells, genomic fragments containing the predicted hairpin and flanking sequences of the mutated microRNA produced 80% less mature form of the microRNA compared to expression of the wild type sequence. When transfected into cells, synthetic microRNAs containing the mismatches were impaired in their ability to repress target transcripts. Therefore, these base mismatches impacted miR-96 biogenesis and reduced mRNA targeting. The miR-96/182/183 cluster is sensory tissue-specific with conserved expression in ciliated neurosensory organs (Weston et al., 2006). The finding that mutated miR-96 leads to progressive hearing loss in two families indicates that this microRNA functions in hair cells of the ear to maintain gene expression profiles required for its normal hearing.

Therapeutic Modulation of microRNAs

Inappropriately expressed or mutated microRNAs cause significant changes in biological pathways that can lead to disease. microRNAs therefore represent potential targets whose selective modulation could alter the course of a disease. For microRNAs whose expression is reduced in the disease state, re-introduction of the mature microRNA into the proper tissue could provide a therapeutic benefit by restoring regulation of target genes. Replacement strategies require delivery vehicles for delivery of double-stranded microRNA mimics. For microRNAs whose expression is increased in the disease state, inhibition of microRNA function through use of anti-miRs could restore proper target gene regulation for therapeutic benefit. Single-stranded, chemically-modified microRNA antagonists can be administered systemically without a delivery vehicle, and they distribute to diverse tissue types (Table 1).

Table 1. Properties of methods to antagonize (anti-miRs) or replace (mimics) microRNA function.
Property Anti-miRs miR Mimics
Form Single stranded Double stranded
Functional bio-distribution Kidney > liver > lymph node > adipose > spleen > bone marrow > lung Liver
Formulation Saline Liposomes, viral vectors
Mechanism Blocks microRNA; relieves post-transcriptional target repression Triggers post-transcriptional target repression
Target mRNA regulation Up Down

In a transgenic mouse model of cardiac failure, Thum et al. (2008) demonstrated that miR-21 levels are increased selectively in fibroblasts of the failing heart, contributing to interstitial fibrosis and cardiac hypertrophy. miR-21 expression was progressively dysregulated with increasing severity of disease, and was up-regulated in other models of cardiac disease as well as in human heart failure. In vivo inhibition of miR-21 with a cholesterol-conjugated anti-miR inhibited fibrosis and attenuated cardiac dysfunction in a mouse pressure-overload-induced disease model. To test the therapeutic potential of miR-21 inhibition in established cardiac disease, mice were subjected to pressure overload of the left ventricle for three weeks prior to anti-miR-21 treatment. During this period, the animals displayed symptoms of cardiac disease, including hypertrophy, fibrosis, and impaired cardiac function. In this therapeutic setting, inhibition of miR-21 led to regression of cardiac hypertrophy and fibrosis. These data demonstrated that antagonizing miR-21 can prevent and even reverse structural and functional deterioration of heart failure in a mouse model.

Members of the let-7 microRNA family are located in chromosomal regions frequently deleted in lung cancer (Calin et al., 2004), and reduced let-7 expression is correlated with poor prognosis in non-small-cell lung cancer (NSCLC) patients (Takamizawa et al., 2004; Yanaihara et al., 2006). Let-7 is thought to function as a tumor suppressor via negative regulation of multiple oncogenes (RAS, MYC, HMGA2) and cell cycle promoters (CDC25A, CDK6, CCND2) (Johnson et al., 2005; Johnson et al., 2007; Mayr et al., 2007; Sampson et al., 2007). Administration of let-7 prevented the onset of tumor formation in a mouse model of NSCLC (Esquela-Kerscher et al., 2008; Kumar et al., 2008). Trang et al. (2009) extended these findings to explore the therapeutic potential of let-7 in established tumors in a lung cancer xenograft mouse model. Exogenous delivery of synthetic let-7b microRNA by intratumoral injection significantly reduced tumor growth, generated enlarged necrotic cores, and reduced NRAS and CDK6 target expression in tumors. Furthermore, intranasal delivery of synthetic let-7 microRNA significantly reduced tumor burden in a K-ras-dependent mouse model of NSCLC. These results demonstrate the therapeutic potential of let-7 in NSCLC and point to microRNA replacement therapy as a promising approach in cancer treatment.

Kota et al. (2009) reported that miR-26a is expressed at lower levels in hepatocellular carcinoma (HCC) cells relative to normal liver tissue. When expressed in liver cancer cells in vitro, miR-26a targets cyclins D2 and E2 and induces cell cycle arrest. Systemic delivery of miR-26a by adeno-associated virus (AAV) reduced tumor burden in a mouse model of HCC, whereas control AAV-treated animals developed fulminant disease. AAV-mediated administration of miR-26a restored miR-26a expression, reduced tumor cell proliferation, and induced apoptosis in tumor cells without affecting survival of normal hepatocytes or causing general toxicity . These results demonstrate that microRNA replacement offers a safe and effective approach to cancer therapy.

Mattes et al. (2009) demonstrated that the expression of several microRNAs, including miR-126, is induced in the airway wall in response to house dust mite exposure in mice. Allergen challenge induced hallmark features of allergic asthma, including airway hyperresponsiveness and inflammation. Antagonism of miR-126 function by intranasal administration of cholesterol-conjugated anti-miR-126 suppressed the asthmatic phenotype, decreasing TH2 response, airway hyperresponsiveness, infiltrating eosinophils and neutrophils, and mucus hypersecretion compared to control-treated mice. These results support a role for miR-126 in the innate host immune response in the lung.

Esau and colleagues (Esau et al., 2006) contributed the first demonstration that inhibition of a microRNA, miR-122, could provide a therapeutic approach to the treatment of disease. miR-122 is selectively and abundantly expressed in the liver, where it comprises ~70% of the total microRNA population. Inhibition of miR-122 by systemic administration of a miR-122 antisense oligonucleotide reduced plasma cholesterol levels and a decrease in hepatic fatty acid and cholesterol synthesis rates in normal mice. miR-122 target transcripts in liver were coordinately de-repressed, which has been confirmed by others (Krutzfeldt et al., 2005; Elmen et al., 2008). The consequences of inhibiting the most abundant microRNA in the liver were surprisingly mild. Even after one month treatment with saturating doses of anti-miR-122, mice appeared healthy, with no overt toxicity. The link between miR-122 inhibition, derepression of miR-122 targets, and decreased plasma cholesterol levels has been extended to disease states where therapeutic administration of anti-miR-122 reduced the level of triglycerides and improved hepatic steatosis in diet-induced obese mice (Esau et al., 2006).

An elegant study by Lanford et al. (2010) recently provided the first demonstration of therapeutic microRNA inhibition in primates. In addition to its role in lipid metabolism, miR-122 is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells (Jopling et al., 2005). The inhibition of miR-122 in liver cells caused an ~80% reduction of replicating hepatitis C viral RNAs, as a result of a direct genetic interaction between miR-122 and the 5′ non-coding region of the viral genome. Studies with replication-defective viral RNAs suggested that miR-122 does not affect mRNA translation or stability, but rather facilitates replication of viral RNA. These data indicate that miR-122 is an essential host factor for HCV replication, and highlight the potential for miR-122 as a target for HCV anti-viral intervention. Therapies that target essential host functions for HCV are particularly attractive because they present an effective approach to anti-viral intervention with a high barrier to resistance.

Lanford et al. (2010) explored the anti-viral potential of anti-miR-122 in chronically HCV-infected chimpanzees. High dose anti-miR-122 produced a significant decrease in HCV RNA in serum after three weeks of treatment, with 2.6 orders of magnitude reduction observed after 14 weeks of treatment. Liver transcripts with miR-122 seed matches in the 3′ UTRs were significantly de-repressed, and interferon-regulated genes were down-regulated. No adaptive mutations in the miR-122 seed sites of the HCV 5′ non-coding region were observed, suggesting an absence of viral resistance. In addition, HCV-induced liver pathology was improved in treated animals. This study provides a striking demonstration of the therapeutic feasibility and safety of microRNA inhibition in a primate disease model.

Table 2. microRNA modulation causes disease phenotypes.
microRNA Validation Phenotype References
Let-7 Genetic, pharmacologic Tumor regression Esquela-Kerscher et al., 2008; Kumar et al., 2008; Trang et al., 2009
miR-1 Genetic Heart disease Zhao et al., 2007
miR-15/-16 Genetic Leukemia Klein et al., 2010
miR-21 Genetic, pharmacologic Reduced heart disease and fibrosis Thum et al., 2008
miR-26a Pharmacologic HCC tumor regression Kota et al., 2009
miR-96 Genetic Hearing loss Lewis et al., 2009; Mencia et al., 2009
miR-126 Genetic Defective angiogenesis Kuhnert et al., 2008; Wang et al., 2008
miR-126 Pharmacologic Reduced lung inflammation Mattes et al., 2009
miR-122 Genetic, pharmacologic Reduced HCV viral load Jopling et al., 2005; Lanford et al., 2010
miR-133 Genetic Heart disease Liu et al., 2008
miR-143/-145 Genetic Hypertension Xin et al., 2009
miR-150 Genetic Leukemia Xiao et al., 2007
miR-155 Genetic Immunosuppression Rodriguez et al., 2007; Thai et al., 2007; Vigorito et al., 2007
miR-189 Genetic Tourette’s syndrome Abelson et al., 2005
miR-206 Genetic Protection against ALS Williams et al., 2009
miR-208 Genetic Heart disease van Rooij et al., 2007
miR-223 Genetic Neutrophilia Johnnidis et al., 2008
miR-375 Genetic Hyperglycemia Poy et al., 2009

Outlook for microRNA Therapeutics

RNA-based therapeutics appear ready to deliver on their promise. Progress is being made with siRNA therapeutics (Davis et al., 2010), and the antisense therapeutic Mipomersen (Raal et al., 2010) is showing success in the clinic. Recent data demonstrate not only that dysregulated microRNAs are associated with and can cause human disease, but that selective modulation of microRNA activity can provide therapeutic benefit in rodents and primates. These exciting data strengthen the case for microRNA modulators as candidate therapeutics. An inhibitor of miR-122 is currently in Phase I clinical trials, becoming the first microRNA therapeutic in humans. The field eagerly awaits the outcome of human safety and efficacy trials for this microRNA modulator. While there is still much to learn about optimal design, chemical modification, and delivery of microRNA modulators, this new class of therapeutics is poised to become a unique approach to treating human disease.


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[Discovery Medicine, 9(47):311-318, April 2010]

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