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Therapeutic RNA-silencing oligonucleotides in metabolic diseases

Nature Reviews Drug Discovery volume 21, pages 417–439 (2022)Cite this article

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Abstract

Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design and optimization of synthetic nucleic acid chemistry, in combination with the development of highly selective and efficient conjugate delivery technology platforms, have established and validated oligonucleotides as a new class of drugs. To date, there are five marketed oligonucleotide therapies, with many more in clinical studies, for both rare and common liver-driven metabolic diseases. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in metabolism, review past and current clinical trials, and discuss ongoing challenges and possible future developments.

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Fig. 1: Applications of antisense RNA and RNAi in metabolic disease.
Fig. 2: siRNA and ASO-based therapies in hypercholesterolaemia.
Fig. 3: Acute hepatic porphyria subtypes and mechanism of ALAS1-siRNA action.
Fig. 4: Oxalate metabolism and RNAi targeting of HAO to reduce oxalate levels.

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Acknowledgements

The authors regret omission of citations of papers that have contributed to the field owing to space limitation. Work in the M.S. laboratory is supported by the Swiss National Science Foundation (SNSF), the NCCR ‘RNA and Disease’ (51NF40-182880), the Novartis Foundation and the Vontobel Foundation. Figures were created with BioRender.com.

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Authors and Affiliations

  1. Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland

    Algera Goga & Markus Stoffel

  2. Medical Faculty, University of Zürich, Zürich, Switzerland

    Markus Stoffel

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  1. Algera Goga
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A.G. and M.S. contributed equally to the development of presented concepts and writing of the manuscript.

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Correspondence to Markus Stoffel.

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M.S. is a member of the scientific advisory board of Alnylam Pharmaceuticals. A.G. declares no competing interests.

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Glossary

Gain-of-function mutations

Mutations in which the altered gene product possesses a new molecular function or a new pattern of gene expression.

Lipid nanoparticle

Non-viral drug delivery system, composed of biodegradable and biocompatible solid lipids and stabilized by emulsifiers, with sizes typically in the range 50–1,000 nm.

PEG–lipid

PEG–lipid Polyethylene glycol (PEG)–lipid conjugates are PEG derivatives that contain phospholipid molecules such as dimyristoyl glycerol (DMG) or 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which have been used in bioconjugation and lipid nanoparticle drug delivery to reduce liposome aggregation and prolong circulation lifetime.

Sarcopenia

A syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength.

Haem

An iron-centred porphyrin and the prosthetic group in many proteins, including haemoglobin and cytochrome P450 enzymes.

Statins

A class of lipid-lowering medications that inhibit HMG-CoA reductase, a rate-limiting enzyme of cholesterol biosynthesis.

Glomerulonephritis

Inflammation of the kidney glomeruli.

Enhancer

A short region of DNA that can be bound by proteins to increase the likelihood that transcription of a particular gene will occur.

Bile acid sequestrants

Resins that bind to negatively charged bile acids and bile salts in the small intestine to interrupt the enterohepatic circulation of bile acids and increase the conversion of cholesterol into bile, thereby lowering LDL-cholesterol.

Steatosis

The accumulation of lipid droplets within hepatocytes, considered pathological when it exceeds 5% of liver weight or affects more than 5% of hepatocytes.

Apolipoprotein

Protein that binds lipid to form lipoprotein and enable lipid transport in the circulation.

Chylomicrons

Lipoprotein particles that consist of dietary triglycerides, phospholipids, cholesterol and proteins produced in the enterocytes that transport lipids in other parts of the body.

Thrombocytopenia

A condition characterized by abnormally low levels of blood platelets that may result in bleeding problems.

Lipodystrophy

A group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue.

Pancreatitis

Inflammation of the exocrine pancreas.

Remnant particles

Products of partially catabolized chylomicrons and VLDL particles, from which some triglycerides have been removed.

Proteinuria

Refers to increased levels of proteins in the urine.

Nephrotic syndrome

A group of kidney disorders that causes too much protein to be lost from the blood into the urine.

Cardiomyopathy

An acquired or hereditary disease of the heart muscle.

Atrial fibrillation

The most common irregular heart rhythm, which starts in the atria, causes poor blood flow and is associated with heart failure, dementia and stroke.

Aneurysms

Ballooning and weakened areas in arteries, often occurring in the aorta, brain, back of the knee, intestine or spleen.

Liver cirrhosis

Chronic liver damage from various causes leading to scarring and liver failure.

NAS

(NAFLD Activity Score). Represents the sum of numerical scores for steatosis (0–3), hepatocellular ballooning (0–2) and lobular inflammation (0–3).

HOMA-IR

Homeostasis model assessment–estimated insulin resistance is an indicator of insulin resistance and is widely used for the estimation of insulin resistance in research. It is calculated from fasting blood glucose (FPG) and insulin (FPI) levels, that is, HOMA-IR = (FPI × FPG)/22.5.

Erythema

Skin rash caused by injured blood capillaries.

Hyperplasia

An enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation.

Arthropathy

A term used for any disease of the joints.

Endocytosis

A cellular process in which substances are brought into the cell.

Haplotype

A group of alleles in an organism that are inherited together from a single parent.

Neurovisceral attacks

Symptoms consisting of autonomic neuropathies such as severe abdominal pain, constipation and vomiting.

Nephrocalcinosis

A condition characterized by the deposition of calcium in the kidney parenchyma and tubules.

Thermogenic metabolism

Refers to the process in which heat production is increased through metabolic stimulation.

Urolithiasis

A small, hard deposit of minerals and salts that forms in the kidneys and is often painful when passed.

Alternative RNA splicing

A process during gene expression that allows a single gene to code for multiple proteins.

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Goga, A., Stoffel, M. Therapeutic RNA-silencing oligonucleotides in metabolic diseases. Nat Rev Drug Discov 21, 417–439 (2022). https://doi.org/10.1038/s41573-022-00407-5

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