Targeting the genetic drivers of disease with nucleotide-based therapeutics
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What are nucleotide-based therapeutics?
Nucleotide-based therapeutics offer huge potential to specifically modulate cellular pathways in ways not previously possible. These therapies include all nucleic-acid-based approaches that work inside cells to affect gene expression – the genetic blueprint of disease – to ultimately change protein expression and potentially alter the course of disease.1
Nucleotides are the basic structural units that make up nucleic acids such as DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Sometimes, nucleotide-based therapeutics are called nucleic acid therapies or therapeutic nucleic acids, for this reason.
What are the advantages of nucleic acid therapies?
A major advantage of nucleic acid-based therapies is they can modulate expression of disease-causing genes, which can have potential therapeutic benefit. By targeting the underlying genetic drivers of disease, nucleic acid therapies offer the potential to achieve long-lasting treatment while supporting a precision medicine approach.1
What are the different types of nucleotide-based therapeutics?
Antisense oligonucleotides (ASOs)
Antisense oligonucleotides (ASOs) are short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest.2, 3 ASOs are single-stranded RNA molecules that offer new opportunities for therapeutic intervention because they act inside the cell to influence protein production.4, 5 Once inside, ASOs bind with high specificity to target mRNA or pre-mRNA, inducing its degradation – effectively silencing it – to prevent its translation into a detrimental protein product. They are a promising approach for the treatment of genetic drivers of disease.
We are currently working to further our precision medicine approaches in non-alcoholic steatohepatitis (NASH), a leading cause of chronic liver disease. NASH occurs when fat builds up in the liver, leading to inflammation and cell damage. This complex disease has numerous drivers, including strong genetic factors, which have been reviewed in the Journal of Hepatology.6 Recent research using omics technologies, such as wide-scale genomics, has enabled identification of new disease-causing gene variants:
PNPLA3
A single nucleotide substitution in the PNPLA3 gene results in a mutation that impairs the breakdown of fat in liver cells which raises the risk of NASH.
Through collaboration with the biotechnology company Ionis Pharmaceuticals and the University of Gothenburg, we are developing an ASO that can target liver cells to ‘silence’ PNPLA3 with the aim of restoring fat break down in the liver. Our preclinical research shows promising results that ASO treatment targeted to PNPLA3 reduces fat accumulation in liver cells.7
HSD17B13
Though some genetic mutations are harmful, others can be protective. For instance, a single nucleotide substitution in HSD17B13 has a protective effect against NASH and fatty liver disease (FLD).8, 9
Together with Ionis Pharmaceuticals, we are investigating how ASOs could mimic the protective effects of the loss-of-function mutation in the HSD17B13 gene.
Small interfering RNA (siRNA)
Similar to ASOs, small interfering RNA (siRNA) are nucleic acids that act inside the cell to modulate gene expression to prevent the production of disease-associated proteins. However, siRNA are double-stranded RNA molecules whereas ASOs are single-stranded.10-12
Through a balanced approach of internally developed technologies and external collaborations with biotechnology companies like Silence Therapeutics, we are identifying and progressing liver-based targets, as well as developing new delivery approaches for targeting other tissues such as the heart, lungs and kidneys. Targeted siRNA delivery to these other tissues represents a new opportunity to treat cardiovascular, renal, metabolic and respiratory diseases.
Messenger RNA (mRNA)
Messenger RNA (mRNA) is the cell’s blueprint for building proteins. It is a single stranded RNA molecule that encodes genetic information from DNA to be translated into functional protein molecules.
mRNA is a compelling therapeutic modality because of its ability to drive high-efficiency, dose-dependent, protein expression which represents a unique approach for regulating aberrant or absent protein function. Combined with state-of-the-art drug delivery systems, such as lipid nanoparticles (LNPs), they offer opportunities for the delivery of a wide range of next generation medicines to patients.12
Self-amplifying RNA (saRNA)
Self-amplifying RNA (saRNA) is a new platform which uses similar technology to mRNA but with the added ability to self-amplify, so proteins are produced for longer, resulting in higher protein levels per dose.
This amplification step could have added advantages in the future production of therapeutics using saRNA requiring much lower and less frequent doses than conventional mRNA to produce the same level of protein.
Latest updates in nucleotide-based therapeutics
Ensuring specific and targeted therapeutic delivery
Lipid nanoparticles (LNPs) are promising and innovative vehicles for intracellular delivery of nucleotide-based therapeutics for production of protein therapeutics in cells. They have a successful track record of delivering nucleic acids and are an advanced approach for mRNA delivery.14,15 For example, we have shown that LNPs can deliver mRNA into cells to initiate cellular protein production after intravenous, subcutaneous and pulmonary administration. Now, we are focusing our research on enhancing the efficacy and safety profile of this drug delivery system.
Oligonucleotide conjugates enable targeting to specific cells and tissues. Without conjugation, the uptake of oligonucleotides in cells is limited and remains a barrier for broadening the scope of this therapeutic modality. Using a linker, we can perform novel conjugation chemistry to attach different drug modalities – small molecules, peptides, antibodies, etc – to direct the oligonucleotide to the tissue of interest.15,16 To target the liver, the state-of-the-art targeting ligand is the N-acetylgalactosamine (GalNAc), which binds a receptor that is highly expressed on hepatocytes in the liver. GalNac conjugation results in strong targeting and subsequent downregulation or deactivation of specific mRNAs in the liver.16,17 To realise the full potential of oligonucleotide therapeutics, we are exploring targeting ligands to other cell types by utilising specific cell-surface receptors that facilitate up-take by the targeted cells. If we can achieve effective targeted delivery of oligonucleotides to specific cells and tissue, we can expand the druggable target space, be able to treat diseases in a better way and ultimately make an impact on patients’ lives.
Quantitative analysis of ASO subcellular distribution
To develop effective ASOs and other nucleotide-based therapeutics, we need to be able to visualise their distribution inside of cells. One good way to do this is by transmission electron micropscope, where a beam of electrons is transmitted through a specimen to form an image. Using nanoscale secondary ion mass spectrometry (nanoSIMs), we can accurately measure drug uptake to better capture pharmokinetic information at the subcellular level.
Working together to advance nucleotide-based therapeutics
Accelerating nucleotide-based therapeutic development through collaborations
Ionis Pharmaceuticals
For nearly a decade, we have partnered with Ionis Pharmaceuticals to discover and develop nucleotide-based therapeutics across numerous disease areas, including cardiovascular, renal, metabolism and oncology. This strategic collaboration aims to ultimately get RNA-targeted treatments to the patients who need them most.
RNA Therapeutics Institute
We are collaborating with the RNA Therapeutics Institute, an academic department at UMass Chan Medical School to optimise antisense oligonucleotides (ASOs). The RNA Therapeutics Institute faculty are recognised as scientific trailblazers, and we are collaborating with Jonathan Watts, a Professor at RNA Therapeutics Institute who has extensive experience in oligonucleotides and drug development.
Silence Therapeutics
In partnership with Silence Therapeutics, we are advancing our siRNA drug discovery efforts to address unmet medical needs in cardiovascular, renal, metabolic (CVRM) and respiratory diseases.
VaxEquity
In collaboration with VaxEquity, we are working to optimise saRNA to target novel pathways not amenable to traditional drug discovery across our therapy areas of interest. This collaboration adds a promising new platform to our drug discovery toolbox with the potential to enable vaccines and a variety of other therapeutic applications.
Gatehouse Bio
Mutations in RNA genes may dysregulate biological pathways that contribute to numerous diseases, including heart failure with preserved ejection fraction (HFpEF). In collaboration with Gatehouse Bio, leveraging its AI-powered Code-Breaker™ Platform, designed to identify novel small RNA mutations, we are closing the gap between RNA modality, AI, and disease biology with the shared goal of developing RNA-based treatments in heart failure.
Join us: Working together to advance nucleotide-based therapeutics
We welcome committed, talented scientists to join us on what promises to be one of the most exciting, stimulating and rewarding journeys in 21st century medicine. We are uniquely positioned to develop cutting-edge nucleotide-based therapeutics, and we are already growing a differentiated pipeline to address targeting to specific cells and tissues to realise the full potential of nucleotide-based therapeutics. By giving our people the resources and support to push the boundaries of science, we are going beyond the ordinary to help improve billions of lives worldwide.
We recruit scientists with relevant expertise to join us in our new state-of-the-art research facilities in Gothenburg, Sweden, Cambridge, UK, and Gaithersburg, US. We are proud of our progress, prepared for the challenges that lie ahead, and confident that, in the next five to 10 years, ASOs and RNA-based therapies will help improve the outlook for patients with some of today’s most serious and life limiting diseases.
References
1. Kulkarni, J.A., Witzigmann, D., Thomson, S.B. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021). https://doi.org/10.1038/s41565-021-00898-0
2. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9-21.
3. Bennett CF. Therapeutic Antisense Oligonucleotides Are Coming of Age. Ann Rev Med. 2019;70:307-321.
4. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017;35(3):238-248.
5. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-Targeted Therapeutics [published correction appears in Cell Metab. 2019 Feb 5;29(2):501]. Cell Metab. 2018;27(4):714-739.
6. Lindén D, Romeo S. Mini-Review for Journal of Hepatology: Therapeutic opportunities for the treatment of NASH with genetically validated targets. J Hepatol. 2023 May 17:S0168-8278(23)00335-5. doi: 10.1016/j.jhep.2023.05.007
7. Lindén D, Ahnmark A, Pingitore P et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab. 2019 Apr;22:49-61.
8. Abul-Husn NS, Cheng X, Li AH, et al. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018;378(12):1096-1106.
9. Gellert-Kristensen H, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase-Lowering Effect of a HSD17B13 Variant. Hepatology. 2020;71(1):56-66.
10. Dana H, Chalbatani GM, Mahmoodzadeh H, et al. Molecular Mechanisms and Biological Functions of siRNA. Int J Biomed Sci. 2017;13(2):48-57.
11. Humphreys SC, Thayer MB, Campbell J, et al. Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development. J Med Chem. 2020;63(12):6407-6422.
12. Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics [published correction appears in Nat Rev Drug Discov. 2019 Mar 18;:] [published correction appears in Nat Rev Drug Discov. 2019 Apr 24;:]. Nat Rev Drug Discov. 2019;18(6):421-446.
13. Yanez Arteta, Marianna, Tomas Kjellman, Stefano Bartesaghi, Simonetta Wallin, Xiaoqiu Wu, Alexander J. Kvist, Aleksandra Dabkowska, et al. 2018. “Successful Reprogramming of Cellular Protein Production through mRNA Delivered by Functionalized Lipid Nanoparticles.” Proceedings of the National Academy of Sciences of the United States of America 115 (15): E3351–60.
14. Maugeri M, Nawaz M, Papadimitriou A, et al. Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells. Nat Commun. 2019;10(1):4333. doi:10.1038/s41467-019-12275-6
15. Nawez M, Hagvall S, Tanhruksa B, et al. Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions. Adv Sci. 2023. https://doi.org/10.1002/advs.202206187
16. Winkler J. Oligonucleotide conjugates for therapeutic applications. Ther Deliv. 2013;4(7):791-809.
17. Seth PP, Tanowitz M, Bennett CF. Selective tissue targeting of synthetic nucleic acid drugs. J Clin Invest. 2019;129(3):915-925.
Veeva ID: Z4-56660
Date of preparation: August 2023