Oligonucleotides are short synthetic DNA or RNA polymers, which modulate gene expression through Watson-Crick base pairing with targeted nucleic acids. Oligonucleotides regulate gene expression through a series of processes, including gene silencing, splicing regulation, non-coding RNA suppression, gene activation, gene editing, and so on. Therefore, this class of drugs has the potential to treat a variety of diseases. At present, there are many kinds of oligonucleotide under development, including antisense oligonucleotide (ASO), small interfering ribonucleic acid (siRNA), microRNA (miRNA) and aptamer.
Antisense oligonucleotides (ASOs) are short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest.
siRNA is a double-stranded RNA molecule that is non-coding. It is also known as silencing RNA and short interfering RNA. miRNAs are implicated in a variety of physiological and pathological processes, including cancer, cell cycle progression, infectious diseases, immunity, diabetes, metabolism, myogenesis, and muscular dystrophy, making them an important target for new drug development.
MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression.
Aptamers are single-stranded DNA or RNA oligonucleotides that bind to specific targets via shape recognition, with high affinity and specificity.
Currently, several small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies have been approved by the FDA, which can lead to the degradation of mRNA through different mechanisms. siRNA and ASO can have beneficial effects on metabolic diseases through several applications. The most obvious application is to inhibit the production of disease-causing proteins that cause disease. These proteins may be due to gain-of-function mutations, resulting in abnormal activity or specificity, or protein aggregation. ASO/RNAi can specifically target mutation-producing alleles, or both mutation-producing and wild-type alleles if mutations occur in non-essential genes. siRNA therapy for transthyroxine amyloidosis (ATTR) is an example of this strategy. They reduce the production of wild-type and variant transthyroxine proteins.
Another way in which ASOs and siRNAs can be used is to target key components in metabolic or signaling pathways that affect cellular stress responses. In this case, disease pathways are often up-regulated due to environmental or genetic pressures, resulting in disease phenotypes. Silencing key components of highly active signaling pathways modulates stress responses and affects disease phenotypes. For example, patients with dysproteinaemias have increased PCSK9 receptor synthesis, which may lead to hypercholesterolemia. Silencing the expression of PCSK9 downregulates overactive signaling pathways and reduces plasma cholesterol levels. ASO and siRNA can also be used to treat metabolic diseases by interfering with feedback signaling pathways and reprogramming metabolic pathways.
Table 1: FDA approved oligonucleotide drugs
| Name, Company | Target (indication) | Organ (ROA) | FDA approval |
| Fomivirsen (Vitravene) Ionis Pharma Novartis | CMV UL123 (cytomegalovirus) retinitis) | Eye (IVI) | August 1998 |
| Pegaptanib (Macugen) NeXstar Pharma Eyetech Pharma | VEGF-165 (neovascular age-related macular degeneration) | Eye (IVI) | December 2004 |
| Mipomersen (Kynamro) Ionis Pharma Genzyme Kastle Tx | APOB (homozygous familial Liver (SQ) hypercholesterolaemla) | Liver (SQ) | January 2013 |
| Defibrotide (Defitelio) Jazz Pharma | NA (hepatic veno-occlusive disease) | Liver (IV) | March 2016 |
| Eteplirsen (Exondys 51) Sarepta Tx | DMD exon 51 (Duchenne muscular dystrophy) | Skeletal muscle (IV) | September 2016 |
| Nusinersen (Spinraza) Ionis Pharma Biogen | SMN2 exon 7 (spinal muscular atrophy) | Spinal cord (IT) | December 2016 |
| Patisiran (Onpattro) Alnylam Pharma | TTR (herediary transthyretin amyloidosis, polyneuropathy) | Liver (IV) | August 2018 |
| Inotersen (Tegsedi) Ionis Pharma Akcea Pharma | TTR (herediary transthyretin amyloidosis, polyneuropathy) | Liver (SQ) | October 2018 |
| Givosiran (Givlaari) Alnylam Pharma | ALAS1 (acute hepatic porphyria) | Liver (SQ) | December 2019 |