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Review
. 2022 May 26;65(10):6975-7015.
doi: 10.1021/acs.jmedchem.2c00024. Epub 2022 May 9.

The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments

Janet M Sasso  1 , Barbara J B Ambrose  1 , Rumiana Tenchov  1 , Ruchira S Datta  1 , Matthew T Basel  2 , Robert K DeLong  3 , Qiongqiong Angela Zhou  1
Affiliations
Review

The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments

Janet M Sasso et al. J Med Chem. .

Abstract

In the past decade, there has been a shift in research, clinical development, and commercial activity to exploit the many physiological roles of RNA for use in medicine. With the rapid success in the development of lipid-RNA nanoparticles for mRNA vaccines against COVID-19 and with several approved RNA-based drugs, RNA has catapulted to the forefront of drug research. With diverse functions beyond the role of mRNA in producing antigens or therapeutic proteins, many classes of RNA serve regulatory roles in cells and tissues. These RNAs have potential as new therapeutics, with RNA itself serving as either a drug or a target. Here, based on the CAS Content Collection, we provide a landscape view of the current state and outline trends in RNA research in medicine across time, geography, therapeutic pipelines, chemical modifications, and delivery mechanisms.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Timeline of major RNA research and development milestones. A more detailed timeline table complete with references is provided as Table S1.
Figure 2
Figure 2
Types of naturally occurring RNA and their cellular functions and localizations
Figure 3
Figure 3
Document publication trends for different types of RNA from 1995 to 2020 as found from the CAS Content Collection. Top two panels: journal publications in absolute numbers and given year percentages. Bottom two panels: patent publications (counted once per patent family) in absolute numbers and given year percentages.
Figure 4
Figure 4
Trends in publication volume for different RNA types in the years 1995–2020. Percentages are calculated with yearly publication numbers for each individual RNA type, normalized by total publications in the years 1995–2020 for the same RNA type. Example: Percentage of circRNA documents in 2020 = (number of circRNA documents in 2020)/(total number of circRNA documents from 1995 to 2020).
Figure 5
Figure 5
Numbers of journal documents and patents related to RNAs for medical use by year.
Figure 6
Figure 6
Percentage of journal documents and patents for various types of RNA used in medical studies including therapeutics, vaccines, and diagnostics.
Figure 7
Figure 7
Number of journal publications and patents for mRNA, miRNA, and CRISPR with applications in therapeutics, vaccines, and diagnostics.
Figure 8
Figure 8
Percentage of publications associated with RNAs in medical applications
Figure 9
Figure 9
Yearly number of patent publications on specific diseases targeted by RNA therapeutics, vaccines, and diagnostics.
Figure 10
Figure 10
Top patent assignees for RNA therapeutics, vaccines, and diagnostics.
Figure 11
Figure 11
Top pharmaceutical companies ranked by the number of RNA therapeutic and vaccine agents in the development pipeline. Counts include RNA agents in company-announced pre-clinical development, in clinical trials, or approved. A single RNA agent can be counted multiple times when applied to multiple diseases.
Figure 12
Figure 12
Types of RNA by company and targeted diseases. *Other: acromegaly, hereditary angioedema, and alcohol use disorder.
Figure 13
Figure 13
Counts of potential therapeutics and vaccines in different stages of development (pre-clinical, clinical, completed, withdrawn, and approved) for the various types of RNA. A full list of collected clinical trials is provided in Table S2.
Figure 14
Figure 14
Percentage of pre-clinical, active, and completed clinical trials by RNA type. Figure rows may not sum to 100% because approved and withdrawn clinical trials are not included in this figure.
Figure 15
Figure 15
Counts of potential therapeutics and vaccines in different development stages (pre-clinical, clinical, completed, withdrawn, and approved) for various disease types. A full list of collected clinical trials is provided in Table S2.
Figure 16
Figure 16
Percentage of pre-clinical, active, and completed clinical trials by disease type. Figure rows may not sum to 100% because approved and withdrawn clinical trials are not included in this figure. *Other: acromegaly, alcohol use disorder, and hereditary angioedema.
Figure 17
Figure 17
An example of RNA structure and modification sites. Green circles, modification sites on the phosphate; red circles, attachment sites for modifications on the ribose; blue circles, attachment sites for modifications on the nucleic acid base: 1-methylpseudouridine (1meΨ), cytosine (C), uridine (U), guanosine (G), and adenosine (A).
Figure 18
Figure 18
Examples of modified and rare bases. R = d-ribose; locations of modifications are shown in blue.
Figure 19
Figure 19
Common modifications on the 2′-hydroxyl group of d-ribose. B = nucleic acid base.
Figure 20
Figure 20
Examples of modified RNA backbones. Backbone 1 shows phosphate–ribose backbone linkages, which include the classic phosphodiester (black), phosphorothioate (blue), and phosphorodithioate (red). The purple ribose, α-l-ribose, has an alternative stereochemistry compared to the normal β-d-ribose moieties shown in black. Backbone 2 is a phosphorodiamidate morpholino (PMO) backbone, backbone 3 is (R)-glycol nucleic acid ((R)-GNA), and backbone 4 is peptide nucleic acid (PNA). B = nucleic acid base.
Figure 21
Figure 21
RNA sequences containing modifications and their distribution with respect to sequence lengths (from the CAS Content Collection). Blue bars: absolute number of modified RNA sequences; orange line: percentage of modified RNA sequences in the total RNA sequences with same sequence length.
Figure 22
Figure 22
Frequencies of modifications of RNA and their distributions based on sequence lengths (CAS Content Collection).
Figure 23
Figure 23
Examples of terminal modifications for therapeutic RNAs: siRNA with 3′ tripartite GalNAc ligand L96 (O in the blue circle can be replaced with S); ASO with a PMO backbone (black) and triethylene glycol; RNA aptamer with double 5′-PEGylation.−
Figure 24
Figure 24
Examples of RNA nanocarriers.
Figure 25
Figure 25
Percentage distribution of RNA nanocarrier-related documents in the CAS Content Collection.
Figure 26
Figure 26
Examples of cationic lipids used as nucleic acid carriers. (An extensive list with the structures of the most frequently used cationic lipids in lipid nanoparticle pharmaceutical formulations according to the CAS Content Collection is available).
Figure 27
Figure 27
Examples of structures of polymeric nucleic acid carriers.
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