**3. Antisense therapeutic interventions in various diseases**

The antisense technology is well placed to influence the developments in human genetics and genomics to generate drugs for the treatment of monogenic and polygenic diseases. The "antisense" are the oligodeoxyribonucleotide molecules complementary to the DNA or RNA sequence of the target gene designed to hybridize specific mRNA. By capitalizing "antisense" DNA approach, the overexpressed proteins can be blocked in several diseases such as cancer, neurological diseases, cardiovascular diseases, inflammation and autoimmune diseases, infectious diseases, etc. [6].

#### **3.1 Antisense therapy for cancer**

The beauty of antisense technology is that it can precisely recognize the DNA location in a gene, a single mRNA class, and can distinguish between the normal and mutated oncogenes in cancer cells. Several studies have confirmed that in cancer patients, this can be used as an inhibitor of gene expression, which will decrease the tumor growth by manipulating the important cellular functions and protein production. By decreasing the specific gene expression, inducing the degradation of target mRNA, and initiating the premature termination of transcription, the antisense therapy can correct the abnormal expression of cellular genes and mutations in tumor cells. One of the major limitations of this approach is nuclease degradation. For this, several strategies are under development. Delivery of antisense oligo or drug to distant as well target tumors is a major hurdle. The development of suitable delivery systems for targeting therapeutic genes and antisense agents into targeted tumor cells and tissues is one of the potential approaches that needs to be further developed and explored. In order to enhance the gene therapy and antisense therapy against a wide variety of cancers and cancer types in future, the development of next generation of carriers will a remarkable progress in the field of gene therapy and could serve as a promising technology for systemic cancer gene therapy and antisense therapy. As we know, cancer has been a major area of therapeutic investigation for antisense technology. Currently, custirsen, a chimeric 2′MOEmodified antisense drug targeting clusterin, is being evaluated in phase III clinical

**5**

*Antisense Therapy: An Overview*

*DOI: http://dx.doi.org/10.5772/intechopen.86867*

**3.2 Antisense therapy for cardiovascular diseases**

with end-stage renal disease on hemodialysis [6, 18, 19].

treatment of chronic refractory pouchitis [21, 24].

**3.4 Antisense therapy in neurological disorders**

**3.3 Antisense therapy for inflammation and autoimmune diseases**

The antisense drugs have been and are currently being evaluated for multiple inflammatory diseases, such as inflammatory bowel disease. The oral drug, mongersen targeting the SMAD7 mRNA, showed the promising effects on patients with ulcerative colitis. Also, alicaforsen drug, targeting intercellular adhesion molecule 1 (CD54), has been tested for its effects by systemic delivery in patients with Crohn's disease [20] as well as in the rectal enema patients with ulcerative colitis (or active unremitting pouchitis) [21–23]. This drug is currently being developed for the

Antisense drugs are being evaluated for multiple neurological diseases and are administered systemically into the cerebrospinal fluid (CSF) that surrounds the brain. Antisense oligonucleotides cannot cross the intact blood–brain barrier efficiently; therefore, they are directly introduced into the CSF or parenchyma to treat brain or spinal cord diseases. Thus, neurological diseases can be approached using different antisense mechanisms and oligonucleotide designs, with single-stranded antisense oligonucleotides and siRNAs used for local therapy [6]. **Duchenne muscular dystrophy** is a progressive, severely disabling, and ultimately lethal neuromuscular disease caused by point mutations, insertions, or chromosomal rearrangements in the dystrophin gene resulting in truncated protein or loss of transcript through nonsense-mediated decay [25]. Because of multiple genomic alterations in Duchenne muscular dystrophy, no single oligonucleotide will address all forms of the disease [6, 25]. Antisense oligonucleotides designed to promote skipping of exon 51 are the most advanced in clinical trials, and the modified phosphorothioate oligonucleotide drug, eteplirsen, is under regulatory review for marketing approval. Additional antisense drugs are currently under development

trials for the treatment of prostate and lung cancers [13]. Also, the antisense drug, AZD9150, which targets signal transducer and activates the transcription 3 (STAT3) in several types of cancers [14] has shown encouraging activity as a single agent in several cancer types. The modified oligonucleotide targeting androgen receptor is in the clinical trial as a possible treatment for prostate cancer [15]. Several additional antisense drugs, including microRNAs and siRNAs, are in early-stage clinical trials.

The first antisense drug, mipomersen, is approved by the FDA as an adjunct therapy for homozygous familial hypercholesterolemia, which reduces apolipoprotein B mRNA levels [16]. Apolipoprotein C III (apoCIII) plays a critical role in the metabolism of triglyceride-rich lipoproteins, and decreased expression is associated with a lower risk of cardiovascular disease [16, 17]. The clinical trial of volanesorsen, an antisense drug, is designed to reduce apoCIII mRNA levels, and the drug is currently being investigated in placebo-controlled phase III clinical trials for the treatment of familial chylomicronemia syndrome and familial partial lipodystrophy. It has been shown that severe factor XI deficiency provides protection against deep vein thrombosis and therefore cardiovascular morbidity and mortality [6]. The antisense drug IONIS-FXIRx can lower the factor XI levels and has the potential to be more effective than conventional anti-thrombotics. A phase II study with IONIS-FXIRx/BAY 2306001 is ongoing to investigate the drug's effects in patients

#### *Antisense Therapy: An Overview DOI: http://dx.doi.org/10.5772/intechopen.86867*

*Antisense Therapy*

diseases, etc. [6].

**3.1 Antisense therapy for cancer**

and affordable cure to many more diseases.

**3. Antisense therapeutic interventions in various diseases**

The antisense technology is well placed to influence the developments in human

The beauty of antisense technology is that it can precisely recognize the DNA location in a gene, a single mRNA class, and can distinguish between the normal and mutated oncogenes in cancer cells. Several studies have confirmed that in cancer patients, this can be used as an inhibitor of gene expression, which will decrease the tumor growth by manipulating the important cellular functions and protein production. By decreasing the specific gene expression, inducing the degradation of target mRNA, and initiating the premature termination of transcription, the antisense therapy can correct the abnormal expression of cellular genes and mutations in tumor cells. One of the major limitations of this approach is nuclease degradation. For this, several strategies are under development. Delivery of antisense oligo or drug to distant as well target tumors is a major hurdle. The development of suitable delivery systems for targeting therapeutic genes and antisense agents into targeted tumor cells and tissues is one of the potential approaches that needs to be further developed and explored. In order to enhance the gene therapy and antisense therapy against a wide variety of cancers and cancer types in future, the development of next generation of carriers will a remarkable progress in the field of gene therapy and could serve as a promising technology for systemic cancer gene therapy and antisense therapy. As we know, cancer has been a major area of therapeutic investigation for antisense technology. Currently, custirsen, a chimeric 2′MOEmodified antisense drug targeting clusterin, is being evaluated in phase III clinical

genetics and genomics to generate drugs for the treatment of monogenic and polygenic diseases. The "antisense" are the oligodeoxyribonucleotide molecules complementary to the DNA or RNA sequence of the target gene designed to hybridize specific mRNA. By capitalizing "antisense" DNA approach, the overexpressed proteins can be blocked in several diseases such as cancer, neurological diseases, cardiovascular diseases, inflammation and autoimmune diseases, infectious

into clinical trials and market for the treatment of a broad variety of diseases, and numerous oligonucleotides are under clinical development [6, 8–10]. The firstgeneration antisense drug, fomivirsen, targeting cytomegalovirus, was approved for the treatment of cytomegalovirus retinitis [11]. Many second-generation drugs are under development and are showing encouraging activity in the clinic. Now oligonucleotide therapy has come a long way and has been established as promising therapeutic tool. During this period, several clinical trials have been performed on thousands of participants for several diseases and only six molecules provided the clear clinical benefit in rigorously controlled trials [10]. As of now, there are six FDA-approved drugs based on oligonucleotide therapy: (1) fomivirsen for treatment of CMV retinitis in AIDS patients, (2) mipomersen for treatment of familial hypercholesterolemia, (3) defibrotide for treatment of veno-occlusive disease in the liver, (4) eteplirsen for the treatment of Duchenne muscular dystrophy, (5) pegaptanib for the treatment of neovascular age-related macular degeneration, and (6) nusinersen for the management of spinal muscular atrophy [10, 12]. In conclusion oligonucleotide-based antisense therapy has provided solutions to untreatable diseases. Future inventions in this technology will help in establishing the better

**4**

trials for the treatment of prostate and lung cancers [13]. Also, the antisense drug, AZD9150, which targets signal transducer and activates the transcription 3 (STAT3) in several types of cancers [14] has shown encouraging activity as a single agent in several cancer types. The modified oligonucleotide targeting androgen receptor is in the clinical trial as a possible treatment for prostate cancer [15]. Several additional antisense drugs, including microRNAs and siRNAs, are in early-stage clinical trials.
