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APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA.
Amyloid ( IF 5.5 ) Pub Date : 2019-10-25 , DOI: 10.1080/13506129.2019.1681392 Christoph Niemietz 1 , Oksana Nadzemova 1 , Andree Zibert 1 , Hartmut H-J Schmidt 1
Amyloid ( IF 5.5 ) Pub Date : 2019-10-25 , DOI: 10.1080/13506129.2019.1681392 Christoph Niemietz 1 , Oksana Nadzemova 1 , Andree Zibert 1 , Hartmut H-J Schmidt 1
Affiliation
The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease. Here, the role of APOE was investigated with regard to the efficacy of Patisiran, the first LNP-siRNA recently approved for clinical use in patients having transthyretin amyloidosis (ATTR amyloidosis). Patisiran was evaluated in the human hepatoma cell line HepG2 after knockdown of APOE. The APOE genotype was determined in ATTR amyloidosis patients treated with Patisiran. TTR knockdown was monitored in consecutive plasma up to week 12. Downregulation of APOE suppressed efficacy of Patisiran in HepG2 cells. TTR levels were found to be robustly reduced (84.7% ± 1%) following Patisiran treatment in patients plasma. Analysis of APOE polymorphisms in ATTR amyloidosis patients revealed three most frequent genotypes E3/3, E3/4 and E3/2. APOE stratification of patients did not show significant differences of TTR plasma concentrations following treatment. Our results suggest that APOE is an important mediator of TTR silencing by Patisiran, however efficacy is independent of the APOE genotype.
中文翻译:
用脂质纳米颗粒siRNA治疗的ATTR淀粉样变性患者的APOE多态性。
以脂质纳米颗粒(LNP)封装的siRNA制剂为代表的新型化合物具有靶向疾病的巨大潜力,尤其是肝脏疾病。LNP的内吞作用被认为是由脂蛋白稳态的重要血清蛋白APOE介导的。APOE多态性影响与肝受体的结合,并与特定疾病的发展有关。在这里,就Patisiran的功效对APOE的作用进行了研究,Patisiran是最近被批准用于转甲状腺素蛋白淀粉样变性病(ATTR淀粉样变性)患者的临床首个LNP-siRNA。敲除APOE后,在人肝癌细胞系HepG2中评估了Patisiran。在经Patisiran治疗的ATTR淀粉样变性患者中确定了APOE基因型。在连续的血浆中监测TTR敲低直至第12周。APOE的下调抑制了Patisiran在HepG2细胞中的功效。在患者血浆中进行Patisiran治疗后,发现TTR水平显着降低(84.7%±1%)。对ATTR淀粉样变性患者的APOE多态性的分析显示了三种最常见的基因型E3 / 3,E3 / 4和E3 / 2。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但功效与APOE基因型无关。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但疗效与APOE基因型无关。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但疗效与APOE基因型无关。
更新日期:2020-04-20
中文翻译:
用脂质纳米颗粒siRNA治疗的ATTR淀粉样变性患者的APOE多态性。
以脂质纳米颗粒(LNP)封装的siRNA制剂为代表的新型化合物具有靶向疾病的巨大潜力,尤其是肝脏疾病。LNP的内吞作用被认为是由脂蛋白稳态的重要血清蛋白APOE介导的。APOE多态性影响与肝受体的结合,并与特定疾病的发展有关。在这里,就Patisiran的功效对APOE的作用进行了研究,Patisiran是最近被批准用于转甲状腺素蛋白淀粉样变性病(ATTR淀粉样变性)患者的临床首个LNP-siRNA。敲除APOE后,在人肝癌细胞系HepG2中评估了Patisiran。在经Patisiran治疗的ATTR淀粉样变性患者中确定了APOE基因型。在连续的血浆中监测TTR敲低直至第12周。APOE的下调抑制了Patisiran在HepG2细胞中的功效。在患者血浆中进行Patisiran治疗后,发现TTR水平显着降低(84.7%±1%)。对ATTR淀粉样变性患者的APOE多态性的分析显示了三种最常见的基因型E3 / 3,E3 / 4和E3 / 2。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但功效与APOE基因型无关。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但疗效与APOE基因型无关。患者的APOE分层在治疗后并未显示出TTR血浆浓度的显着差异。我们的结果表明,APOE是Patisiran抑制TTR沉默的重要介体,但疗效与APOE基因型无关。