Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 323

7

Antisense Oligonucleotides and
RNA Interference

Gitanjali Kher, Sonia Trehan, Ambikanandan Misra
Pharmacy Department, TIFAC - Centre of Relevance and Excellence in New
Drug Delivery Systems, The Maharaja Sayajirao University of Baroda,
PO Box 51, Kalabhavan, Vadodara 390 001, Gujarat, India

7.1 Introduction

Antisense technology presents an opportunity to manipulate gene expression within
cells to treat an endless number of diseases and is a powerful tool for studying gene
function. The antisense approach utilizes antisense agents to fight various diseases
by regulating the expression of a specific factor, the presence of which actually
causes that particular disease. Some antisense approaches have evolved over the last
few decades, explicitly the introduction of antisense oligonucleotides (AS ODNs)
by Stephenson and Zamecnik in the late 1970s [1] , the description of ribozymes
by Cech and colleagues in the 1980s [2] , and the demonstration of short interfering
RNA (siRNA) by Fire and Mello in the 1990s [3] . Recently, microRNA (miRNA)
replacement therapy has emerged as a new approach to treat human diseases like
cancer and various neurodegenerative diseases. Replacement therapy involves the
reintroduction of a synthetic version of a natural miRNA that gets depleted in the
diseased tissue [4] .
Highly specific and effective gene silencing of any disease can be achieved by an
accurate knowledge of the target mRNA sequence and rational design of its comple-
mentary antisense agents for the downregulation of its protein message. Thus, these
are being extensively explored for personalized therapy of cancer, HIV, and other
mutating viral diseases [5-8] . Gene silencing also has a great potential as a chemo-
sensitizing agent to overcome the difficulties of drug resistance and dose-limiting
toxicities of chemotherapeutic agents [9] . This technique differs from that used with
conventional drugs in that it precisely checks the formation of disease-causing pro-
tein by downregulating its expression, rather than relieving the symptoms of the dis-
ease after its manifestation. Moreover, this technique can be differentiated from the
genetic approach by its action on the mRNA, expressing the disease-causing protein
rather than acting on a particular faulty gene. The success of this approach relies on
understanding the correct sequence of RNA that carries the protein message respon-
sible for the disease of interest. Fortunately, the completion of the human genome
project endows us with a rich source of information on target genes, for the rational
design of antisense drugs within hours, for research and clinical trials.