Control of backbone chemistry and chirality boost oligonucleotide splice switching activity.
Nucleic Acids Res
; 50(10): 5443-5466, 2022 06 10.
Article
em En
| MEDLINE
| ID: mdl-35061895
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos Antissenso
/
Distrofia Muscular de Duchenne
/
Oligonucleotídeos Fosforotioatos
Limite:
Animals
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos