RESUMO
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.
Assuntos
Doenças Cardiovasculares , Hepatócitos , Humanos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/química , Análise Custo-Benefício , RNA de Cadeia Dupla , Acetilgalactosamina/química , Proteína 3 Semelhante a AngiopoietinaRESUMO
OBJECTIVE: To observe the therapeutic effect of Equiguard in old patients with Shen-yang deficiency syndrome (SYDS). METHODS: Twenty old patients with diagnosis matching the criteria of SYDS selected from out-patients were administered with Equiguard capsule 3 times per day, 0.70 g each time for 3 successive months. The changes in general condition, peripheral blood picture, function of the liver and kidney, and sex hormones before and after treatment were observed. The changes in the American Urinary Surgery Association (AUA) score of prostatism, urosis and residue urine in the urinary bladder were also estimated. RESULTS: After the 3-month treatment, no significant change was found in the patients' general condition, peripheral blood picture, liver and kidney function and sex hormones, while the symptoms of prostatism and urosis were markedly improved (P<0.01), and the volume of residue urine in the urinary bladder was obviously reduced. CONCLUSION: Equiguard shows a significant therapeutic effect in treating old patients with SYDS, which could effectively improve the symptoms of prostatism and urosis in patients and is highly safe.