Control of backbone chemistry and chirality boost oligonucleotide splice switching activity
Author:
Kandasamy Pachamuthu1, McClorey Graham2, Shimizu Mamoru1, Kothari Nayantara1, Alam Rowshon1, Iwamoto Naoki1, Kumarasamy Jayakanthan1, Bommineni Gopal R1, Bezigian Adam1, Chivatakarn Onanong1, Butler David C D1, Byrne Michael1, Chwalenia Katarzyna2, Davies Kay E3, Desai Jigar1ORCID, Shelke Juili Dilip1, Durbin Ann F1, Ellerington Ruth2, Edwards Ben3, Godfrey Jack1, Hoss Andrew1, Liu Fangjun1, Longo Kenneth14, Lu Genliang1, Marappan Subramanian1, Oieni Jacopo2, Paik Ik-Hyeon1, Estabrook Erin Purcell1, Shivalila Chikdu1, Tischbein Maeve1, Kawamoto Tomomi1, Rinaldi Carlo24ORCID, Rajão-Saraiva Joana3, Tripathi Snehlata1, Yang Hailin1, Yin Yuan1, Zhao Xiansi1, Zhou Cong1, Zhang Jason1, Apponi Luciano1, Wood Matthew J A24, Vargeese Chandra1ORCID
Affiliation:
1. Wave Life Sciences , Cambridge, MA, USA 2. Department of Paediatrics, University of Oxford , South Parks Road, Oxford OX1 3QX, UK 3. Department of Physiology, Anatomy and Genetics, University of Oxford , South Parks Road, Oxford OX1 3PT, UK 4. MDUK Oxford Neuromuscular Centre, University of Oxford , Oxford OX2 9DU, UK
Abstract
Abstract
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.
Funder
Wave Life Sciences
Publisher
Oxford University Press (OUP)
Reference65 articles.
1. Exon-skipping therapy: a roadblock, detour, or bump in the road?;Hoffman;Sci. Transl. Med.,2014 2. Therapeutic developments for duchenne muscular dystrophy;Verhaart;Nat. Rev. Neurol.,2019 3. Current and emerging treatment strategies for duchenne muscular dystrophy;Mah;Neuropsychiatr. Dis. Treat.,2016 4. Diagnosis and management of duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management;Birnkrant;Lancet. Neurology,2018 5. Function and genetics of dystrophin and dystrophin-related proteins in muscle;Blake;Physiol. Rev.,2002
Cited by
24 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|