**6.6 Viral vectors**

Viral vector administration and encoding of miRNAs have been used for various therapeutic purposes [51]. A range of viruses can be employed for these purposes, including lentiviruses, adenoviruses, and adenoassociated viruses (AAVs). Since these vectors do not integrate into the genome, they can be eliminated efficiently with minimal toxicity, yet show remarkable efficiency in transferring RNA-encoding vectors into the nucleus of mammalian cells, ensuring high expression of miRNA [51]. Previous studies have shown that systemic lentivirus delivery of miR-15a/16 reduces lymphocytic leukemia progression in a mouse model [52]. In a murine model of muscular dystrophy-associated chronic dilated cardiomyopathy [53], intraventricular delivery of AAV vectors containing miR-669a induces long-term miR-669a overexpression and significantly decreases hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Furthermore, it significantly reduces adverse remodeling and enhances systolic

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certain cancer [47].

*Therapeutic Implication of miRNA in Human Disease DOI: http://dx.doi.org/10.5772/intechopen.82738*

**7. miRNA therapeutics in disease**

**7.1 Therapeutic potential of microRNAs in cancer**

**7.2 Therapeutic potential of microRNAs in liver disease**

Numerous studies have demonstrated that alterations in intracellular miRNAs correlated with various liver diseases [28, 38, 61]. In the liver, MiR-122 is one of the highly abundant miRNAs that affects various genes involved in hepatic cholesterol and lipid metabolism, thereby playing a central role in maintaining liver homeostasis [61]. Intriguingly, miR-122 is essential to the stability and propagation of hepatitis C virus (HCV) [61]. The finding of the role of miR-122 in the HCV replication process is one of the best examples of the potential targeted miRNA-based therapeutic

in the following sections.

fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage [53]. Viral vector therapies have shown the highest efficacy for delivering miRNA into cells and organs in vitro and

miRNAs are abundant in many mammalian cell types and appear to target about 60% of the genes of humans and other mammals [54]. Many miRNAs are evolutionarily conserved, which implies that they have important biological functions. However, growing evidence suggests that alteration of miRNAs expressions plays a key role in the development of disease. The signature miRNAs associated with disease and their potential therapeutics in the most common diseases are discussed

Rapidly growing evidence supports that miRNAs play key roles in the pathogenesis of cancer and many miRNAs can function either as oncogenes or tumor suppressors [55]. MiRNAs can influence the development, progression, and metastasis of cancers [29, 30]. Their functional effect may differ depending on their expression levels. They have either an oncogenic potential or tumor-suppressor effect depending on their downstream impact on target genes and thereby controlling the biologic manifestations of cancers. The activity of a lost or down-regulated tumor suppressor miRNA can be restored by using miRNA mimics [56]. To date, there are some miRNA-based trials for treatment of cancers. For examples, miR-34 is one of the tumor suppressor miRNAs and it is significantly downregulated in many kinds of cancer [57]. Therefore, a cancer therapy synthetic miR-34 (MRX34) has been developed and has entered phase I clinical trial for liver cancer and metastasis from other cancers (NCT01829971) [57]. In lung cancer, miR-27a has been reported to be a potential targeted therapy for lung cancer [58]. MicroRNA-loaded minicells (miR-16-based mimic miRNA) are designed to counteract the loss of the miR-15 and miR-16 family and are used in clinic trials for small-cell lung cancer and mesothelioma [59]. The miR-205BP/S3 is a possible promising therapeutic modality for melanoma [60]. Let-7 is well recognized as one of the important tumor suppressors. So re-expression of the tumor-suppressor let-7 is another proposed miRNA therapeutic strategy to upregulate tumor-suppressor miRNA by exogenously transfecting with pre-let-7 that led to the inhibition of growth [27]. In addition to tumor suppressor miRNAs, some of the miRNAs can be served as oncogenes and used as therapeutic targets for cancer. For example, miR-21 is significantly overexpressed in many types of human cancers, thus miR-21 is a potential therapeutic target for a

in vivo. However, their safety and toxicity remains a controversial issue.

*Antisense Therapy*

**6.4 Small molecule inhibitors**

ment of therapeutics.

**6.5 miRNA mimics**

**6.6 Viral vectors**

sequence [44, 45]. The miRNA-masking method, in which only specific mRNA is

Several drugs may possess the ability to modulate miRNA expression, targeting signaling pathways in miRNA biogenesis, ultimate converging on the activation of transcription factors involved in the regulation of miRNA encoding genes. The first specific molecule founded to be effective for inhibition of miRNA is an azobenzene [46]. The authors have demonstrated that the azobenzene can inhibit miRNA-21 by inhibiting miRNA-21 precursor in live cells [46]. MicroRNA-21 is significantly overexpressed in many types of human cancers, thus miR-21 is a potential therapeutic target. Recently, Naro et al. [47] have reported that, using a luciferase-based reporter assay, a high-throughput screen of >300,000 compounds led to the discovery of a new aryl amide class of small-molecule miR-21 inhibitors. Their studies further found that four aryl amide derivatives were very potent and selective miR-21 inhibitors [47]. The small molecule miRNA inhibitors are currently limited by their relatively low potencies and issues with specificity to a particular miRNA, however, they are much easier to deliver and have the promise for develop-

In addition to miRNA inhibition as a major miRNA therapeutic approach, miRNA replacement treatment with miRNA mimics should be another miRNA therapeutic approach in disease associated with decreased miRNAs expressions. Synthetic miRNA mimics can assume the regulatory role of natural miRNAs. In diseases such as cancer, some tumor suppression-related miRNAs are downregulated. Therefore, artificial double-stranded miRNA (miRNA mimic) has been introduced to inhibit cancer [48]. Recent studies have reported that miRNA-34 is a master regulator of tumor suppression and a well-defined miRNA tumor suppressor [49]. It acts on several cancer relevant cellular pathways, including the p53 and wnt/βcatenin pathways. Down-regulation of miR-34 expression has been found in many tumor types, including lung, liver, breast, and colon carcinoma, and treatment with miR-34 mimic has been shown to inhibit tumor growth and progression [49, 50]. Consequently, miR-34 mimic, the first miRNA replacement therapy, is headed to the clinic for treatment of cancer [49, 50]. Replacement of oncosuppressor miRNAs

Viral vector administration and encoding of miRNAs have been used for various therapeutic purposes [51]. A range of viruses can be employed for these purposes, including lentiviruses, adenoviruses, and adenoassociated viruses (AAVs). Since these vectors do not integrate into the genome, they can be eliminated efficiently with minimal toxicity, yet show remarkable efficiency in transferring RNA-encoding vectors into the nucleus of mammalian cells, ensuring high expression of miRNA [51]. Previous studies have shown that systemic lentivirus delivery of miR-15a/16 reduces lymphocytic leukemia progression in a mouse model [52]. In a murine model of muscular dystrophy-associated chronic dilated cardiomyopathy [53], intraventricular delivery of AAV vectors containing miR-669a induces long-term miR-669a overexpression and significantly decreases hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Furthermore, it significantly reduces adverse remodeling and enhances systolic

with their mimics provides an effective strategy against cancer.

masked, may lead to more specific and safer therapeutic strategies.

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fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage [53]. Viral vector therapies have shown the highest efficacy for delivering miRNA into cells and organs in vitro and in vivo. However, their safety and toxicity remains a controversial issue.
