Oligonucleotide-Based Therapeutics: An Emerging Strategy for the Treatment of Chronic Liver Diseases.

Abstract

Chronic liver disease is an important cause of morbidity and mortality in the United States. Despite significant advances, the treatment options for many chronic liver diseases are limited. Recently, oligonucleotide-based therapeutics emerged as a novel treatment approach for a number of liver diseases. Therapeutic oligonucleotides comprised of 15 to 30 nucleotides in length that work in complementary to a specific region of a messenger RNA (mRNA) encoding a disease-related protein or a regulatory non-coding RNA and interfere with the target gene expression. These oligonucleotides can bind with high affinity and specificity through RNA-RNA or RNA-DNA base-pairing and targets the expression of mRNA leading to the disease control. A large number of druggable targets including miR-122, miR-132, miR-34, HSP 47, PNPLA3, STK25 etc., have emerged as susceptible molecular targets in the liver to treat various diseases. Thus, chronic liver diseases may be treated effectively by modulating these susceptible molecular targets using novel therapeutic oligonucleotides. Currently, several preclinical and clinical studies are underway to evaluate the clinical effectiveness and safety of different oligonucleotide therapies in the treatment of chronic liver diseases. In order to optimize its clinical effectiveness, various strategies have been explored including chemical modifications of the oligonucleotides and developing effective drug delivery systems such as oligonucleotide -ligand conjugates, oligonucleotide-polymer conjugates, and lipid or polymer-based nano-carriers. In this review, we provide an overview of the historical perspectives, the mechanism of action, delivery technologies, and clinical experience of using oligonucleotide-based therapies in treating liver diseases.