**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

approaches. Blocking miR-122 using antisense approaches has reduced HCV replication in animal model [61]. MiR-122 binds to two closely spaced target sites (S1 and S2) in the highly conserved 5′ untranslated region of the HCV genome, thereby forming an oligomeric miR-122–HCV complex that protects the HCV genome from nucleolytic degradation or from host innate immune responses. Recently, a LNAmiR-122, known as Miravirsen, has been introduced and demonstrated that it can decrease HCV in nonhuman primates with no side effects [62]. Furthermore, in clinical trials of Miravirsen (NCT01200420), it has shown that the use of miravirsen in patients with chronic HCV genotype 1 infection can induce dose-dependent reductions in HCV RNA levels without evidence of viral resistance [61]. This miRNAbased therapeutics might deliver promising outcomes in the setting of liver disease.

## **7.3 Therapeutic potential of microRNAs in heart disease**

Growing evidence shows miRNAs could be a promise molecular therapeutic strategy for cardiovascular disease [63, 64]. Previous studies have demonstrated that miRNA-21 level is upregulated in activated fibroblasts of the failing heart [65]. The investigators further demonstrated in an *in vivo* study of a mouse model of pressure-overload-induced heart disease that administration of a miRNA-21 antisense construct reduces the extent of heart fibrosis and overall heart function [65]. Their findings validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting. The miR-15 family is also found to be significantly increased in cardiac diseases [66]. Knockdown of the miR-15 family with LNA-modified anti-miRNAs resulted in reduced infarct size after ischaemia-reperfusion injury [66], suggesting it could serve as a therapeutic target for the manipulation of cardiac remodeling and function in the setting of myocardial infarction.

Diastolic dysfunction is a major clinical syndrome. Gain- and loss-of-function studies in animal model have shown that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling. Furthermore, therapeutic inhibition of miR-208a by subcutaneous delivery of miR-208a antisense during hypertension-induced heart failure in rats can prevent pathological myosin switching and cardiac remodeling and improve cardiac function [67, 68]. These studies suggest that miR-208 can serve as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression. In addition, miRNAs also play an important role in regulation of cardiovascular angiogenesis. AntimiR-92a (MRG-110) is currently used as a Phase I clinical trial for Miragen and it could offer a potential therapeutic to accelerate the healing process and revascularization in chronic ischemic disease. MRG-110 is being developed under a license and collaboration agreement with Servier for the treatment of heart failure and other ischemic disease [www.miragen.com]. To date, there is another therapeutics miRNA (MGN-5804 which targeting miR-378) in the development phase for the treatment of cardiovascular disease.

### **7.4 Therapeutic potential of microRNAs in renal disease**

MicroRNAs can serve as mediators and therapeutic targets in many chronic renal diseases [69].

A variety of miRNAs are specifically enriched in the renal tissue as compared with other tissues, including miR-192, miR-194, miR-204, miR-215, and miR-216 [69]. miR-192 is one of the key miRNAs which is involved in diabetic nephropathy [70]. The authors reported that, in individual biopsies, tubulointerstitial fibrosis and low estimated GFR are associated with a decrease in miR-192 expression [70].

**103**

regulated.

Parkinson's disease.

**8. Future prospects**

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

kidney disease-affected mice [72].

**7.5 Therapeutic potential of microRNAs in neurological disease**

miR-192 targets E-cadherin, resulting in fibrosis of tubular cells and development of diabetic nephropathy. These findings suggests that miR-192 mimics should potentially be used as therapeutics of diabetic nephropathy. A global expression profiling study have shown that miR-21 is one of the most highly regulated miRNAs in kidneys of mice with diabetic nephropathy [71]. It has been reported that miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression, which suggests that therapeutic miR-21 silencing could ameliorate diabetic kidney disease. Indeed, in a mouse model of chronic kidney disease, treatment with antagomir against miR-21 reverses both glomerular and tubular cell damage, resulting in a decrease in renal fibrosis and prolonging the life span of the chronic

Some of the miRNAs are highly abundant in the nervous system, where they play key roles in developmental neurobiology. Numerous studies have shown a dysregulation of miRNAs in neurological disease [73, 74]. These alterations in miRNAs expression prior to the onset of or during the course of disease pathology raises the possibility that expressing or inhibiting specific miRNAs might ameliorate the disease process and provide an effective therapeutic strategy. For example, Alzheimer's disease (AD) is being tested for potential miRNA-based therapy [75]. It has reported that a member of the miR-15/107 superfamily, miR-16 can specifically inhibits the expression of AD biomarkers Aβ and Tau, as well as brain inflammation and oxidative stress. MicroR-16 mimics delivered into the brain of mice resulted in a reduction of AD-related genes expression in a region-dependent manner, thus supporting the potential of miR-16 as an excellent therapeutic candidate for treatment of Alzheimer's disease. Similar to the changes of miRNAs in Alzheimer's disease, numerous miRNAs in human and animal models are also reported to be dysregulated in Parkinson's disease [76]. Some of these dysregulated miRNAs have been suggested to be potential therapeutic targets for Parkinson's disease. For example, Cho et al. had suggested that overexpression of miR-205 by miR-205 mimic could provide a potential therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in Parkinson's disease [77]. In addition, it has been reported that early downregulation of miR-34b/c in Parkinson's disease triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability [78]. Therefore, upregulation of miR-34b/c may be an applicable therapeutic strategy for

As the miRNA field dramatically grows, a better understanding of miRNA biogenesis and path-physiologic function will help to develop miRNA-based therapies. In addition, it is well known that a specific miRNA could target multiple genes and affect different organs in the same time. Therefore, research efforts should try to maximize the benefit of target diversity and prevent off-target effects. To achieve this goal, improvement of the chemical design of miRNA antisense and mimics and developing novel delivery systems are very important to ensure that the desired miRNA concentrations are achieved in organs and the targets are specifically

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

*Antisense Therapy*

approaches. Blocking miR-122 using antisense approaches has reduced HCV replication in animal model [61]. MiR-122 binds to two closely spaced target sites (S1 and S2) in the highly conserved 5′ untranslated region of the HCV genome, thereby forming an oligomeric miR-122–HCV complex that protects the HCV genome from nucleolytic degradation or from host innate immune responses. Recently, a LNAmiR-122, known as Miravirsen, has been introduced and demonstrated that it can decrease HCV in nonhuman primates with no side effects [62]. Furthermore, in clinical trials of Miravirsen (NCT01200420), it has shown that the use of miravirsen in patients with chronic HCV genotype 1 infection can induce dose-dependent reductions in HCV RNA levels without evidence of viral resistance [61]. This miRNAbased therapeutics might deliver promising outcomes in the setting of liver disease.

Growing evidence shows miRNAs could be a promise molecular therapeutic strategy for cardiovascular disease [63, 64]. Previous studies have demonstrated that miRNA-21 level is upregulated in activated fibroblasts of the failing heart [65]. The investigators further demonstrated in an *in vivo* study of a mouse model of pressure-overload-induced heart disease that administration of a miRNA-21 antisense construct reduces the extent of heart fibrosis and overall heart function [65]. Their findings validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting. The miR-15 family is also found to be significantly increased in cardiac diseases [66]. Knockdown of the miR-15 family with LNA-modified anti-miRNAs resulted in reduced infarct size after ischaemia-reperfusion injury [66], suggesting it could serve as a therapeutic target for the manipulation of cardiac remodeling and

Diastolic dysfunction is a major clinical syndrome. Gain- and loss-of-function studies in animal model have shown that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling. Furthermore, therapeutic inhibition of miR-208a by subcutaneous delivery of miR-208a antisense during hypertension-induced heart failure in rats can prevent pathological myosin switching and cardiac remodeling and improve cardiac function [67, 68]. These studies suggest that miR-208 can serve as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression. In addition, miRNAs also play an important role in regulation of cardiovascular angiogenesis. AntimiR-92a (MRG-110) is currently used as a Phase I clinical trial for Miragen and it could offer a potential therapeutic to accelerate the healing process and revascularization in chronic ischemic disease. MRG-110 is being developed under a license and collaboration agreement with Servier for the treatment of heart failure and other ischemic disease [www.miragen.com]. To date, there is another therapeutics miRNA (MGN-5804 which targeting miR-378) in the development phase for the

MicroRNAs can serve as mediators and therapeutic targets in many chronic renal

A variety of miRNAs are specifically enriched in the renal tissue as compared with other tissues, including miR-192, miR-194, miR-204, miR-215, and miR-216 [69]. miR-192 is one of the key miRNAs which is involved in diabetic nephropathy [70]. The authors reported that, in individual biopsies, tubulointerstitial fibrosis and low estimated GFR are associated with a decrease in miR-192 expression [70].

**7.3 Therapeutic potential of microRNAs in heart disease**

function in the setting of myocardial infarction.

treatment of cardiovascular disease.

**7.4 Therapeutic potential of microRNAs in renal disease**

**102**

diseases [69].

miR-192 targets E-cadherin, resulting in fibrosis of tubular cells and development of diabetic nephropathy. These findings suggests that miR-192 mimics should potentially be used as therapeutics of diabetic nephropathy. A global expression profiling study have shown that miR-21 is one of the most highly regulated miRNAs in kidneys of mice with diabetic nephropathy [71]. It has been reported that miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression, which suggests that therapeutic miR-21 silencing could ameliorate diabetic kidney disease. Indeed, in a mouse model of chronic kidney disease, treatment with antagomir against miR-21 reverses both glomerular and tubular cell damage, resulting in a decrease in renal fibrosis and prolonging the life span of the chronic kidney disease-affected mice [72].

### **7.5 Therapeutic potential of microRNAs in neurological disease**

Some of the miRNAs are highly abundant in the nervous system, where they play key roles in developmental neurobiology. Numerous studies have shown a dysregulation of miRNAs in neurological disease [73, 74]. These alterations in miRNAs expression prior to the onset of or during the course of disease pathology raises the possibility that expressing or inhibiting specific miRNAs might ameliorate the disease process and provide an effective therapeutic strategy. For example, Alzheimer's disease (AD) is being tested for potential miRNA-based therapy [75]. It has reported that a member of the miR-15/107 superfamily, miR-16 can specifically inhibits the expression of AD biomarkers Aβ and Tau, as well as brain inflammation and oxidative stress. MicroR-16 mimics delivered into the brain of mice resulted in a reduction of AD-related genes expression in a region-dependent manner, thus supporting the potential of miR-16 as an excellent therapeutic candidate for treatment of Alzheimer's disease. Similar to the changes of miRNAs in Alzheimer's disease, numerous miRNAs in human and animal models are also reported to be dysregulated in Parkinson's disease [76]. Some of these dysregulated miRNAs have been suggested to be potential therapeutic targets for Parkinson's disease. For example, Cho et al. had suggested that overexpression of miR-205 by miR-205 mimic could provide a potential therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in Parkinson's disease [77]. In addition, it has been reported that early downregulation of miR-34b/c in Parkinson's disease triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability [78]. Therefore, upregulation of miR-34b/c may be an applicable therapeutic strategy for Parkinson's disease.
