Oligonucleotide (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. Oligonucleotides are a diverse class of therapeutics that are divided into many different classes, such as antisense, aptamers, miRNA, shRNA, siRNA and other types of oligonucleotides.
Antisense oligonucleotides are short, single-stranded DNA molecules that bind to mRNA and have the ability to modify protein expression through a variety of mechanisms. As indicated earlier, therapeutic antisense oligonucleotides are generally made up of 18 to 30 base pairs (bp). Examples of antisense therapeutics that have been approved by the FDA till date include nusinersen (treatment of multiple forms of spinal muscular atrophy (SMA)), eteplirsen (treatment of duchene muscular dystrophy (DMD)) and inotersen (treatment of familial amyloid polyneuropathy (FAP)).
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.
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.
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. 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 mechanism 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.
The Evolving Landscape of Antisense Oligonucleotide Therapeutics
During our research, we identified 7 marketed drugs, 80 clinical stage drugs and 88 drug development programs for the treatment of various oncological and non-oncological indications.
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The market is dominated by small and mid-sized firms based in North America and Europe. Among the molecules developed by these players, five have been approved for different indications in regions, such as the US, Japan, Canada and the UK. Further, nearly 60% of the therapeutics in the pipeline are being evaluated by the players based in North America.
It is worth highlighting that seven molecules have been commercialized till date; this constitutes only 4% of the total number of therapies, which indicates that antisense oligonucleotide therapeutics market has witnessed significant growth in the recent years. Further, over 40% molecules are in clinical stages of development; of these close to 60 molecules are in advanced phases (phase II and above).
Further, majority of the therapies (30) are designed for administration through subcutaneous route. The subcutaneous route of administration facilitates rapid onset of therapeutic action that can be extended to a longer duration.
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This field has witnessed a continuous increase in the number of trials registered per year, representing a CAGR of ~21% between 2010 and 2019. This can be attributed to the continuous increase in the initiatives being taken by several industry and non-industry players that are actively evaluating the therapeutic effectiveness of antisense oligonucleotide based therapies for a wide range of indications.
Several organizations have extended financial support to aid research efforts in this domain; currently, the focus, in terms of funds disbursed, is primarily in support of investigations of drugs for treating neurological conditions
The rising interest in this field is reflected in the number of partnerships inked by the various stakeholders across different application areas
The future opportunity, in terms of revenues from the sales of marketed and late-stage therapies, is anticipated to be well distributed across different disease areas, types of molecules and key geographical regions
The market is expected to witness steady growth over the coming decade; the opportunity will be dispersed across different generations, routes of administration and various types of therapies.
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. 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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