Posters
« Back
Intelligent Delivery of Oligonucleotide Drugs
EP38624
Poster Title: Intelligent Delivery of Oligonucleotide Drugs
Submitted on 12 Apr 2022
Author(s): Sunny Fang
Affiliations: Biopharma PEG Scientific Inc.
Poster Views: 376
View poster »


Poster Information
Abstract: Due to physicochemical properties, unmodified free oligonucleotides are not only quickly cleared by the body after drug delivery, but also have the risk of off-target and toxic side effects. Therefore, nucleic acid drugs require both chemical modification and suitable delivery systems to achieve therapeutic efficacy. Chemical modifications play an important role in the delivery of oligonucleotide drugs, but it is still difficult for small interfering RNA (siRNA) drugs to reach the target site through chemical modifications alone. Delivery of antisense oligonucleotide (ASO) drugs is also poor, making delivery systems critical for success in oligonucleotide drug development. At present, the leading companies in siRNA drug development have their own or licensed delivery technology platforms. siRNA drug delivery systems are relatively mature in various types of nucleic acid drug development, and this article will discuss the delivery technology of nucleic acid drugs from the delivery systems of siRNA drugs.

Delivery System of Marketed siRNA Drugs
To date, four siRNA therapeutics have been approved for commercial application, including ONPATTRO®, GIVLAARI™, OXLUMO™ and Leqvio® .

We can divide the in vivo process of siRNA drugs into three main phases, in each of which the body sets up a different biological barrier for siRNA drugs.

Arrival at the Target Tissue: After administration, siRNA has to escape degradation by nucleases in plasma and tissues and capture by the immune system to arrive at the target tissue smoothly.
Entry into Cells: Due to the large molecular weight and negative surface charge of the siRNA drug, it cannot pass freely through the cell membrane even if it arrives at the target tissue and needs to enter the cell through cytokinesis.
Endo-lysosomal Escape: siRNA has to achieve escape before endosomal binding to lysosomes, entering the cytoplasm, and binding to the target mRNA to achieve gene silencing. [1]
The main mission and responsibility of the delivery system are to protect the siRNA to cross all biological barriers and reach the cytoplasm smoothly to bind to the target mRNA, which in turn silences the gene to exert its drug effect.

Lipid Nanoparticle Delivery System
Due to the inherent charge characteristics of siRNA, cationic liposomes appear to be the best candidates for delivery systems. However, the toxicity of traditional cationic liposomes has hindered the development of siRNA drugs. Alnylam has brought a breakthrough in the successful delivery of oligonucleotides through the use of Arbutus' ionizable cationic lipids. In 2018, Onpattro, the first siRNA drug using lipid nanoparticles as a delivery system, was approved for marketing for the treatment of polyneuropathy caused by hereditary transthyretin amyloidosis (hATTR).
Summary: In recent years, the development of RNA-silencing oligonucleotide therapies is emerging as a hot spot for new drug development. Oligonucleotides can be mainly classified into antisense oligonucleotides(ASO), RNA interference (RNAi) and aptamer RNAs according to their molecular types. Currently, several small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies have been approved for marketing by the FDA. However, the delivery of this type of drug is still in urgent need of furthReferences: 1. Jie Wang, et al., Delivery of siRNA Therapeutics Barriers and Carriers, The AAPS Journal, 2010
2. Akin Akinc, et al., The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs, Nature Nanotechnology, 2019
3. Aaron D. Springer, et al., GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics, Nucleic Acid Therapeutics, 2018
4. Jayesh A. Kulkarni, et al., The current landscape of nucleic acid therapeutics, Nature Nanotechnology, 2021
5. Tracy S. Zimmermann, et al., Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate, Molecular Therapy, 2017
Report abuse »
Questions
Ask the author a question about this poster.
Ask a Question »

Creative Commons

Related Posters


Vertical phenotyper: small footprint device for high-throughput phenotyping of small plants and seedlings
Pavel Mazura, Pavel Klimeš, Lukáš Spíchal

RNA Binding Protein Immunoprecipitation (RIP)
Creative BioMart

Automated colour etching of aluminium alloys
Ondřej Ambrož, Jan Čermák, Patrik Jozefovič, Šárka Mikmeková

Effects of etchant stirring on the surface quality of the metallography sample
Ondřej Ambrož, Jan Čermák, Patrik Jozefovič, Šárka Mikmeková

RWE Thought Experiment: Could RWE Have Prevented Today's Opioid Epidemic? Lessons from 19th Century China
Sheila Mahoney MBA, LifeSciHub LLC, William John, MD, Duke Medical School, Luo Zhou, Chinese Studies Librarian Duke University Libraries