Gene Therapy Drugs Based on Synthetic Oligonucleotides

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Abstract

The development of medicines, the structure of which resembles or is completely identical to the natural components of a living organism, is currently a promising and of great interest among scientists. The invention of a synthetic analog of nucleic acids was carried out due to the active development of oligonucleotide synthesis in the 1980s and subsequent research in the field of chemical modification of the nucleotide, which made it possible to change the properties of nucleic acids and increase their stability. The accumulated world experience has made it possible to create medicines based on synthetic oligonucleotides aimed at the treatment of rare genetic diseases. Since 1998, a relatively small number of drugs have been approved by regulatory authorities in different countries for use in clinical practice. Most of them are aimed at the treatment of orphan diseases. To date, there are 20 therapeutic drugs based on synthetic oligonucleotides that have been approved by medical regulatory authorities for use in clinical practice. Of this list, only one drug was developed in Russia (MIR 19®). This review describes all drugs based on synthetic oligonucleotides approved for 2024, and also examines and systematizes current knowledge about promising types of therapeutic oligonucleotides with different mechanisms of interaction with the target.

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About the authors

I. B. Kozlov

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Author for correspondence.
Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

O. A. Gerasimov

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

O. Y. Domasheva

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

L. G. Bushina

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

L. A. Safonova

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

V. V. Makarov

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

V. S. Yudin

Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical and Biological Agency

Email: IKozlov@cspfmba.ru
Russian Federation, ul. Pogodinskaya 10/1, Moscow, 119121

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Supplementary files

Supplementary Files
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2. Fig. 1. The mechanism of action of therapeutic nucleic acids: (a) transcript cleavage mediated by the interaction of RNase H with the duplex of the hapmer and mRNA; (b) – modulation of the splicing site shift process due to the formation of a steric block mediated by complementary binding of ASA to pre-mRNA. SSO binding sites often act as enhancers or suppressors of splicing, and double-stranded SSO pre-mRNA can block RNA–RNA or RNA-protein interactions that regulate the splicing process. The drawing is adapted from [105].

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3. 2. Cleavage of messenger RNA (mRNA) under the action of the RNA-induced splicing (RIC) complex and si RNA by activating the mechanism of RNA interference.

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4. Fig. 3. The mechanism of target recognition by the aptamer.

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