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RNA Therapeutics: How Far Have We Gone?

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Book cover The mRNA Metabolism in Human Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1157))

Abstract

In recent years, the RNA molecule became one of the most promising targets for therapeutic intervention. Currently, a large number of RNA-based therapeutics are being investigated both at the basic research level and in late-stage clinical trials. Some of them are even already approved for treatment. RNA-based approaches can act at pre-mRNA level (by splicing modulation/correction using antisense oligonucleotides or U1snRNA vectors), at mRNA level (inhibiting gene expression by siRNAs and antisense oligonucleotides) or at DNA level (by editing mutated sequences through the use of CRISPR/Cas). Other RNA approaches include the delivery of in vitro transcribed (IVT) mRNA or the use of oligonucleotides aptamers. Here we review these approaches and their translation into clinics trying to give a brief overview also on the difficulties to its application as well as the research that is being done to overcome them.

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Abbreviations

2′-F:

2′-fluoro

2′-MOE:

2′-O-methoxyethyl

2′-O-CH2Py(4):

2′-O-methyl-4-pyrimidine

2′-OMe:

2′-O-methyl

AADC:

Aromatic L-amino Acid Decarboxylase

AAVs:

Adeno-associated Viruses;

AGO:

Argonaute

AMD:

Age-related Macular Degeneration

AONs:

Antisense Oligonucleotides

ASGPR:

Asialoglycoprotein receptor

ASGR:

Asialoglycoprotein Receptor

BBB:

Blood Brain Barrier

BMD:

Becker Muscular Dystrophy

CNS:

Central Nervous System

CPPs:

Cell-penetrating Peptides

CRISPR:

Clustered Regulatory Interspaced Short Palindromic Repeats

CRISPR-Cas 9:

CRISPR-associated protein 9 (Cas9)

CSF:

Cerebrospinal Fluid

DLin-MC3-DMA:

Anionic lipid dilinol eylmethyl-4-dimethyl-aminoburyate

DMD:

Duchenne Muscular Dystrophy

dsRNAs:

double-stranded RNAs

ExSpeU1s:

Exon-Specific U1 snRNAs

FH:

Familial Hypercholesterolemia

GalNAc:

N-acetylgalactosamine

GPCRs:

G Protein-coupled Receptors

HCV:

Hepatitis C Virus

hFVII:

Human Factor VII

hTTRA:

Hereditary Transthyretin Amyloidosis

I2S:

Iduronate 2-sulfatase

IVT:

in vitro transcribed

LDL-C:

Low-density Lipoprotein Cholesterol

LNAs:

Locked Nucleic Acids

LNPs:

Lipid-based Nanoparticles

miRNAs:

microRNAs

mNIS+7:

Modified Neurologic Impairment Score +7

mRNA:

messenger RNA

NDA:

New Drug Application

PCK9:

Proprotein Convertase Subtilisin/Kexin Type 9

PD:

Pharmacodynamics

PILs:

Pegylated immunoliposomes

PIWI:

P-element induced wimpy testis

PK:

Pharmacokinetics

PMOs:

Phosphoroamidate Morpholino Oligomers

PNAs:

Peptide Nucleic Acids

PS:

Phosphorothioate

RIS:

RNA-induced silencing complex

RNAi:

RNA interference

RNP:

Ribonucleoprotein

RTK:

Human Receptor Tyrosine Kinase

SELEX:

Systematic Evolution of Ligands by Exponential enrichment

sgRNA:

single guide RNA

shRNA:

short hairpin RNA

siRNAs:

small interference RNAs

SLNs:

Solid Lipid Nanoparticles

Sm:

Smith antigen

SMA:

Spinal Muscular Atrophy

SNALPs:

Nucleic-acid-lipid-particles

SSOs:

Splice Switching Oligonucleotides

TLRs:

Toll-like Receptors

TTR:

Transthyretin

U.S. FDA:

U.S. Food and Drug Administration

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Authors and Affiliations

  1. Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal

    Maria Francisca Coutinho, Liliana Matos, Juliana Inês Santos & Sandra Alves

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  1. Maria Francisca Coutinho
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  2. Liliana Matos
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  3. Juliana Inês Santos
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  4. Sandra Alves
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Correspondence to Sandra Alves .

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  1. Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisboa, Portugal, Faculty of Sciences, BioISI – Biosystems & Integrative Sciences Institute, University of Lisbon, Lisboa, Portugal

    Luísa Romão

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Coutinho, M.F., Matos, L., Santos, J.I., Alves, S. (2019). RNA Therapeutics: How Far Have We Gone?. In: Romão, L. (eds) The mRNA Metabolism in Human Disease. Advances in Experimental Medicine and Biology, vol 1157. Springer, Cham. https://doi.org/10.1007/978-3-030-19966-1_7

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