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


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.

SUBMITTER: Kandasamy P 

PROVIDER: S-EPMC9178015 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Kandasamy Pachamuthu P   McClorey Graham G   Shimizu Mamoru M   Kothari Nayantara N   Alam Rowshon R   Iwamoto Naoki N   Kumarasamy Jayakanthan J   Bommineni Gopal R GR   Bezigian Adam A   Chivatakarn Onanong O   Butler David C D DCD   Byrne Michael M   Chwalenia Katarzyna K   Davies Kay E KE   Desai Jigar J   Shelke Juili Dilip JD   Durbin Ann F AF   Ellerington Ruth R   Edwards Ben B   Godfrey Jack J   Hoss Andrew A   Liu Fangjun F   Longo Kenneth K   Lu Genliang G   Marappan Subramanian S   Oieni Jacopo J   Paik Ik-Hyeon IH   Estabrook Erin Purcell EP   Shivalila Chikdu C   Tischbein Maeve M   Kawamoto Tomomi T   Rinaldi Carlo C   Rinaldi Carlo C   Rajão-Saraiva Joana J   Tripathi Snehlata S   Yang Hailin H   Yin Yuan Y   Zhao Xiansi X   Zhou Cong C   Zhang Jason J   Apponi Luciano L   Wood Matthew J A MJA   Vargeese Chandra C  

Nucleic acids research 20220601 10


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 the  ...[more]

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