Stopping the disease production line in its tracks

Antisense oligonucleotides (ASOs) are short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest. Typically, an ASO is a single-stranded sequence complementary to the sequence of the target gene’s transcribed messenger RNA (mRNA) within a cell.1,2

ASOs offer new opportunities for therapeutic intervention because they act inside the cell to influence protein production.3,4 Once inside the cell, the ASO binds to the target mRNA or pre-mRNA, inducing its degradation and preventing the mRNA from being translated into a detrimental protein product. They are a promising approach for the treatment of genetic drivers of disease. 

Our goal is to exploit the full potential of antisense oligonucleotides as novel therapeutic interventions, supported by our deep understanding of new and emerging disease targets across our therapy areas.

Shalini Andersson Chief Scientist & Head of Oligonucleotide Discovery, Discovery Sciences, R&D

One of our molecules, in collaboration with Ionis Pharmaceuticals, targets the mRNA for APOL1 and has shown encouraging results in preclinical models.5 Several variants of the APOL1 gene evolved in sub-Saharan West Africa providing protection from Trypanosoma infections, but people carrying two copies of these variants have an increased risk for developing chronic kidney disease (CKD).6 APOL1 knockdown through ASOs is being explored with the aim of being a precision medicine in CKD and, if successful, would provide a novel treatment option for patients with APOL1-mediated CKD.

As part of our collaboration with Ionis, we are also investigating an ASO targeting FOXP3, previously considered an ‘undruggable target’. FOXP3 is a protein critically involved in the function of T regulatory cells, which are key mediators of immunosuppression in multiple tumour types. Preclinical data demonstrate the downregulation of FOXP3 in T regulatory cells, resulting in anti-tumor activity either added as a single compound or in combination with immune checkpoint targeting compounds.7


1. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9-21.

2. Bennett CF. Therapeutic Antisense Oligonucleotides Are Coming of Age. Ann Rev Med. 2019;70:307-321.

3. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017;35(3):238-248.

4. 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.

5. Aghajan M, Booten SL, Althage M, et al. Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1-transgenic mice. JCI Insight. 2019;4(12):e126124. Published 2019 Jun 20.

6. Dummer PD, Limou S, Rosenburg AZ et al. APOL1 kidney disease risk variants – an evolving landscape. Semin Nephrol. 2015. 35(3): 222–236.

7. Ding M, Brengdahl J, Lindqvist M, et al. A Phenotypic Screening Approach Using Human Treg Cells Identified Regulators of Forkhead Box p3 Expression. ACS Chem Biol. 2019;14(3):543-553.

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