Preface

Antisense therapy, or oligotherapy, is an emerging field of disease treatment and a revolution that has completely changed gene therapy. Antisense oligonucleotides are small synthetic fragments of DNA that have potential to target and bind to messenger RNA of a particular gene causing a particular disease, and modulate specific protein production in human genome. Antisense therapy using oligonucleotides has many applications in clinical medicine and has great potential to change the therapeutic landscape for many disease conditions, including their prevention, treatment, and management. This book presents oligonucleotides as an important therapeutic option and discusses how they may be used to treat cancer and other diseases. It not only covers important developments in the field of molecular mechanisms, but also highlights novel therapeutic approaches in several human disorders including cancer. There was a need to bring this information together in a single volume, as much of the recent developments are dispersed throughout biomedical literature, largely in specialized journals.

It is my hope that readers will appreciate the complexity of oligonucleotides research, especially for healthcare treatment. In the era of precession medicine, targeted therapy plays an important role. Identifying disease-specific molecular changes and targets for precision treatment is critical. In theory, oligonucleotides are designed to control the transfer of genetic information, but the use of antisense therapy is likely to benefit the patient and help manage disease. This book summarizes the current state of the field of oligo-based therapy in cancer and is an ideal resource for clinicians and researchers interested in antisense therapy. It will also appeal to physicians, surgeons, residents, biomedical scientists, and students.

> **Shashwat Sharad, Ph.D.**  Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of Health Sciences (USU) and Walter Reed National Military Medical Center (WRNMMC), Bethesda, Maryland, USA

Henry Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA

#### **Suman Kapur, Ph.D.**

Senior Professor, Department of Biological Sciences and Dean, International Programmes and Collaboration Division (University wide), Birla Institute of Technology and Science, Pilani Hyderabad Campus, Telangana, India

**1**

**Chapter 1**

**Abstract**

*Shashwat Sharad*

Antisense Therapy: An Overview

Nucleic acids are the backbone of antisense therapy. Antisense oligonucleotidebased therapeutics involves downregulation of gene expression. RNA-based drugs that include antisense oligonucleotides bear great therapeutic potential toward treatment of various diseases by altering RNA and/or reducing, restoring, and modifying protein expression through multiple molecular mechanisms. Pharmacology of targeted antisense therapy has provided the platform to translate its utility to the clinic. Over the years, chemical modifications of antisense oligonucleotides have not only enhanced the specificity and efficacy but also reduced the side effects. These have changed the whole clinical trial design and provide newer strategies for therapies. Improvement in antisense oligonucleotide therapy technology has allowed and brought research from bench to clinic. Additionally, the use of small interfering RNAs, micro RNAs, ribozymes, and other antisense compounds toward the treatment of deadly diseases like cancers have demonstrated both preclinical and clinical responses. Furthermore, antisense therapy has great potential to target specific genes of interest in the context of precision medicine. Optimization of enhanced delivery, specificity, affinity, and nuclease resistance with reduced toxicity is underway in different disease context. This chapter gives a complete overview of antisense therapy and highlights its potential. Here, we focused on the advances of the antisense technology, pharmacology, therapeutics, and drug discovery.

**Keywords:** antisense oligonucleotides, antisense therapy, antisense drug,

The advancement in the next-generation sequencing enables us to identify the genetic heritages of several diseases, such as cancer, Parkinson's, rheumatoid arthritis, and Alzheimer's, which brings to attention the development of personalized medicine [1]. This knowledge has been well adapted and accepted for diagnosis, but the field still lags toward pharmaceutical interventions to address the genetic defects underlying diseases. At present, small molecules and proteins are the two major classes of US Food and Drug Administration (FDA)-approved drugs [2]. Small-molecule drugs inhibit target proteins through competitive binding, whereas protein-based drugs (such as antibodies) can bind with high specificity to several targets. The size and stability of proteins are the major limitations of their utility for majority of disease targets [2], and both protein and small-molecule drugs cannot target every disease-relevant protein or gene. Thus, there is a current need to develop the drugs for personalized genomics. The mRNA- and DNA-based drugs are therapeutically more promising and have the great potential to cure the genetic defect [1]. The RNA-based drugs have emerged as a promising candidate to treat

antisense therapeutic, gene therapy

**1. Introduction: antisense technology**
