Oligonucleotides

Oligonucleotides are nucleic acid polymers with specially designed sequences, including antisense oligonucleotides (ASOs), siRNA (small interfering RNA), microRNA and aptamers. Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing.

Most of oligonucleotides (ASOs, siRNA and microRNA) hybridize with the target gene mRNA or pre-mRNA through complementary base pairing, and can theoretically selectively regulate any target gene and protein expression, including many “undruggable” targets. The aptamers have a high affinity to the target protein similar to antibodies by the tertiary structure, rather than sequence. Oligonucleotides also have additional advantages, including relatively simple production and preparation technology, short development cycle, and long lasting effect.

The utilization of oligonucleotides as drugs is a fundamentally novel approach compared to conventional small molecule inhibitors. The potential of Oligonucleotides in precision genetics has raised enthusiasm for applications in cancer, cardiovascular diseases, and rare diseases therapies. The recent FDA approvals of Givosiran, Lumasiran and Viltolarsen have ushered the wave of RNAi or RNA-based therapies into the mainstream of drug development.

References:

[1] Khan P, et al. Mol Cancer. 2021;20(1):54.

[2] Damase TR, et al. 2021;9:628137.

[3] Kim YK. Chonnam Med J. 2020;56(2):87-93.

[4] Roberts TC, et al. Nat Rev Drug Discov. 2020;19(10):673-694.

The central problem preventing the widespread implementation of gene therapies based on RNA and DNA polymers is delivery. The complexity of the problem is enormous. Naked RNA or DNA molecules are rapidly degraded in biological fluids, do not accumulate in target tissues following systemic administration, and cannot penetrate into target cells even if they get to the target tissue. Further, the immune system is exquisitely designed to recognize and destroy vectors containing genetic information.

To overcome the barriers to safe and effective nucleic acids delivery, scientists have developed both viral-vector based and non-viral delivery systems (liposomes) that protect the nucleic acids from degradation, maximize delivery to on- target cells and minimize exposure to off- target cells. Here, we focus on non-viral delivery systems that have advantages of ease of manufacture, reduced immune responses, multi-dosing capabilities, larger payloads, and flexibility of design. The lead non-viral delivery systems are lipid nanoparticles (LNPs).The origins of LNP systems lie in the development of liposomal drug delivery systems for small molecule drugs. Now, lipid nanoparticles have been extensively investigated and are currently the most advanced vector for the delivery of genetic drugs (for example, oligonucleotides and RNA vaccines), as evidenced by the approval of Patisiran for treatment of Amyloidosis in the US and EU in 2018.

References:

[1] Cullis PR, et al. Mol Ther. 2017;25(7):1467-1475.

[2] Kulkarni JA, et al. Nat Nanotechnol. 2021;16(6):630-643.

[3] Paunovska K, et al. Nat Rev Genet. 2022;1-16.

[4] Khalid A. Hajj, et al. Nat Rev Mater 2, 17056 (2017).

[5] Roberts TC, et al. Nat Rev Drug Discov. 2020;19(10):673-694.

Nucleosides and nucleotides are the building blocks of life. Through phosphorylation and polymerization, these building blocks are transformed into nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Five major nucleoside bases are common in human biology, including the purines (two-ring structure) adenine and guanine and the pyrimidines (one-ring structure) cytosine, uracil, and thymine. Nucleosides and nucleotides are closely involved in the preservation and transmission of the genetic information of all living creatures. In addition, they play roles in biological energy storage and transmission, signaling, regulation of various aspects of metabolism, and even an important role as an antioxidant.

In addition, the development of Polymerase Chain Reaction (PCR) methodology has brought a dramatic change and rapid development in studies of DNA. Meanwhile, chemically synthesized oligonucleotides have been studied as potential antisense DNAs, siRNAs and DNA aptamers; as oligonucleotide therapeutic agents, primers for PCR method, and elements of DNA computers.

Messenger RNA (abbreviated mRNA) is a type of single-stranded RNA involved in protein synthesis. mRNA is made from a DNA template during the process of transcription. The role of mRNA is to carry protein information from the DNA in a cell’s nucleus to the cell’s cytoplasm (watery interior), where the protein-making machinery reads the mRNA sequence and translates each three-base codon into its corresponding amino acid in a growing protein chain.

Pharmaceutical excipients are the substances formulated alongside the active ingredient of a medication. These excipients play a significant role in the production, application, and efficacy of drugs and are closely related to the formulation's shaping, stability, final product quality, and pharmacokinetic characteristics. During the preparation of pharmaceutical formulations, the selection of excipients directly impacts the drug's bioavailability, toxic side effects, adverse reactions, and clinical efficacy.