1. Oligonucleotides


Oligonucleotides (113)


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.



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Drug Delivery Systems

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.



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