Antisense Oligonucleotide Therapeutics


Oligonucleotides (commonly referred to as oligos), are short single stranded DNA or RNA molecules, typically containing 15-20 nucleotide residues. In the modern biopharmaceuticals and biotechnology, the applications of these molecules are vast, including (but not limited to) genetic testing, fundamental biomolecular research, and forensic analysis. Presently, researchers are actively exploring the applications of oligonucleotides as pharmacological interventions for the treatment of various diseases (especially cancer, genetic disease and rare diseases). There are two principle approaches used for the development of RNA-based drugs; double stranded RNA-mediated interference (RNAi) and antisense oligonucleotides (ASO). Both approaches are currently in clinical trials for targeting of RNAs involved in various diseases, such as cancer and neurodegeneration.

  • RNA Interference Therapeutics

RNAi is a natural process of post-transcriptional gene silencing, involving short strands of nucleic acids. Cells use this process to silence and / or inhibit gene expression, via the targeted degradation of specific (unwanted) mRNA molecules. From an application perspective, the gene specificity of RNAi is the primary reason why it is being considered for therapy development. In theory, RNAi based therapeutics are capable of treating indications, such as age-related macular degeneration (AMD), hepatitis C and various forms of cancer, which are generally perceived as hard to treat with conventional pharmacological options. The basic mechanism of RNAi is a three step process of gene silencing.

  • Antisense Oligonucleotide Therapeutics

Antisense oligonucleotides (also known as ASOs) are short RNA / DNA based structures whose sequence specifically binds to the target RNA and inhibits the gene expression. They have a sequence that is complementary to a sequence within a specific mRNA. Antisense therapeutics are considered to be one of the most promising agents for impairing the protein production and blocking the function of the specific target gene of interest in the human genome. Presently, this process forms the basis for many therapeutics being investigated in different stages of clinical trials for treatment of a range of cancers, viral diseases, and genetic disorders. Antisense oligonucleotides are designed to target the mRNA using a number of different mechanisms.

With the success of the first antisense oligonucleotide, fomivirsen, approved in 1998 for the treatment of disease cytomegalovirus (CMV) retinitis, the field of antisense oligonucleotide therapeutics has evolved rapidly with multiple approved / late stage clinical candidates and a long preclinical pipeline. With the ability to interfere with the process of gene expression, antisense oligonucleotides are considered to be one of the best options for gene manipulation and impairment of protein production. These therapeutic interventions have shown to have potential to treat a variety of disorders, including oncological disorders, genetic diseases, hepatic diseases, respiratory disorders and infectious diseases.

Amongst the recent developments, important to mention that certain companies are evaluating the therapeutic efficacy of antisense RNA (which are different from the conventional antisense DNA). These antisense RNAs read in the opposite direction of the coding strand and bind to the coding strand of mRNAs and further, prevent them from being expressed. In fact, oligonucleotide drug developers have also begun investigating the relevance of these interventions against the novel Coronavirus (COVID-19). We believe that a breakthrough in this disease area is likely to provide a significant impetus. Given the pace of innovation and developments in this upcoming market, we can expect antisense oligonucleotides to become a major therapeutic modality in the foreseen future.

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