RAMON ERITJA*, CARME FÀBREGA
*Corresponding author
Research Professor IQAC-CSIC, CIBER-BBN, ISCIII, Barcelona, Spain

Abstract

Oligonucleotide-based therapeutics is considered a major drug development area for the upcoming years. Research in this field has led to the discovery of new mechanisms for the regulation of genes expression. In addition, it has allowed the development of new strategies for the preparation of drugs that act at the level of gene expression, modulating the production of proteins responsible for causing diseases. However, it took huge effort that last around 30-40 years to demonstrate the validity of this approach. In this manuscript, we will go over the main developments of the area.

INTRODUCTION
The research of new drugs to treat diseases considered “undruggable”, such as genetic disorders, has led to the use of complex molecules, such as, antibodies, nucleic acids and others. Although the idea of taking advantage of the base pairing properties of oligonucleotides to design specific drugs to inhibit gene expression is present in the bibliography since the early 70’s (1), Zamecnik and Stephenson in 1978 demonstrated for the first time the inhibition of Rous sarcoma virus replication (2). The development of the phosphoramidites (3) and the outbreak of the HIV (4) triggered the interest for the first antisense studies, mainly focused on the development of antiviral oligonucleotides (Chart 1). At that time, one of us was doing his postdoctoral training at the Beckman Research Institute of City of Hope and, later on, at the University of Colorado at Boulder. At City of Hope we had the chance of preparing oligonucleotides carrying methylphosphonates linkages (Figure 1), following the methodology described by Dr. Miller’s group (5). A series of short oligonucleotides complementary to the first splice acceptor site of the tat-3 gene ...