Control of backbone chemistry and chirality boost oligonucleotide splice switching activity.

Autor:	Kandasamy P; Wave Life Sciences, Cambridge, MA, USA., McClorey G; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK., Shimizu M; Wave Life Sciences, Cambridge, MA, USA., Kothari N; Wave Life Sciences, Cambridge, MA, USA., Alam R; Wave Life Sciences, Cambridge, MA, USA., Iwamoto N; Wave Life Sciences, Cambridge, MA, USA., Kumarasamy J; Wave Life Sciences, Cambridge, MA, USA., Bommineni GR; Wave Life Sciences, Cambridge, MA, USA., Bezigian A; Wave Life Sciences, Cambridge, MA, USA., Chivatakarn O; Wave Life Sciences, Cambridge, MA, USA., Butler DCD; Wave Life Sciences, Cambridge, MA, USA., Byrne M; Wave Life Sciences, Cambridge, MA, USA., Chwalenia K; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK., Davies KE; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK., Desai J; Wave Life Sciences, Cambridge, MA, USA., Shelke JD; Wave Life Sciences, Cambridge, MA, USA., Durbin AF; Wave Life Sciences, Cambridge, MA, USA., Ellerington R; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK., Edwards B; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK., Godfrey J; Wave Life Sciences, Cambridge, MA, USA., Hoss A; Wave Life Sciences, Cambridge, MA, USA., Liu F; Wave Life Sciences, Cambridge, MA, USA., Longo K; Wave Life Sciences, Cambridge, MA, USA.; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford OX2 9DU, UK., Lu G; Wave Life Sciences, Cambridge, MA, USA., Marappan S; Wave Life Sciences, Cambridge, MA, USA., Oieni J; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK., Paik IH; Wave Life Sciences, Cambridge, MA, USA., Estabrook EP; Wave Life Sciences, Cambridge, MA, USA., Shivalila C; Wave Life Sciences, Cambridge, MA, USA., Tischbein M; Wave Life Sciences, Cambridge, MA, USA., Kawamoto T; Wave Life Sciences, Cambridge, MA, USA., Rinaldi C; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford OX2 9DU, UK., Rajão-Saraiva J; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK., Tripathi S; Wave Life Sciences, Cambridge, MA, USA., Yang H; Wave Life Sciences, Cambridge, MA, USA., Yin Y; Wave Life Sciences, Cambridge, MA, USA., Zhao X; Wave Life Sciences, Cambridge, MA, USA., Zhou C; Wave Life Sciences, Cambridge, MA, USA., Zhang J; Wave Life Sciences, Cambridge, MA, USA., Apponi L; Wave Life Sciences, Cambridge, MA, USA., Wood MJA; Department of Paediatrics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford OX2 9DU, UK., Vargeese C; Wave Life Sciences, Cambridge, MA, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2022 Jun 10; Vol. 50 (10), pp. 5443-5466.
DOI:	10.1093/nar/gkac018
Abstrakt:	Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited clinical benefit due to poor pharmacology. To overcome limitations of existing technologies, we engineered chimeric stereopure oligonucleotides with phosphorothioate (PS) and phosphoryl guanidine-containing (PN) backbones. We demonstrate that these chimeric stereopure oligonucleotides have markedly improved pharmacology and efficacy compared with PS-modified oligonucleotides, preventing premature death and improving median survival from 49 days to at least 280 days in a dystrophic mouse model with an aggressive phenotype. These data demonstrate that chemical optimization alone can profoundly impact oligonucleotide pharmacology and highlight the potential for continued innovation around the oligonucleotide backbone. More specifically, we conclude that chimeric stereopure oligonucleotides are a promising splice-switching modality with potential for the treatment of neuromuscular and other genetic diseases impacting difficult to reach tissues such as the skeletal muscle and heart. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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