Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.
Mol Ther
; 32(3): 637-645, 2024 Mar 06.
Article
en En
| MEDLINE
| ID: mdl-38204163
ABSTRACT
N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Cardiovasculares
/
Hepatocitos
Tipo de estudio:
Health_economic_evaluation
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article