Senior Director, BioScience Metabolism, CVRM, 澳门第一赌城在线娱乐R&D、澳门在线赌城娱乐



Associate Principal Scientist, Translation Science and Experimental 药物, CVRM, 澳门第一赌城在线娱乐R&D、澳门在线赌城娱乐


非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝炎(NASH)在世界范围内是导致肝脏疾病的主要原因,预计其数量还会上升. NASH has a significant unmet medical need with no approved drugs. 对NASH生物学的新认识和潜在的新的基因验证药物靶点有希望为患者提供有效的治疗.

NASH是慢性的, progressive liver disease in which fat accumulates in liver cells (steatosis), causing inflammation and injury. 这可能导致疤痕组织(纤维化)和肝损伤,最终可能需要移植.1 Progressive NASH can also lead to a liver cancer called 肝细胞癌 (HCC),甚至死亡.1 诊断困难和对NASH机制缺乏了解意味着治疗方案有限.

幸运的是,这种情况似乎正在改变,预计精准医疗将发挥关键作用.2 澳门第一赌城在线娱乐的 精密医学 approach – targeting the right patient, with the right medicine aims to improve outcomes for NASH patients.

组学技术, such as wide-scale genomics, has enabled identification of new disease-causing 基因 variants. 事实上, research has shown that in the PNPLA3基因, 单核苷酸替代会严重损害肝细胞的正常脂肪分解,并显著增加发生所有NAFLD特征的风险, with up to a 10 fold higher risk of developing HCC.An other example is for the the HSD17B13 基因, 单核苷酸取代导致该酶功能丧失(LoF), confers a protective effect against NASH, 纤维化, 肝硬化, HCC and liver-related mortality.4,5

Learn more about how we want to target the PNPLA3 基因 as a potential 精密医学 in the below video:

In further research published in April 2022 in 自然的新陈代谢, 研究人员 described a 基因 variant in PSD3 which has a protective effect against NASH and fatty liver disease (FLD).6  澳门第一赌城在线娱乐的 scientists and collaborators also showed that downregulation of PSD3 降低肝细胞内脂质水平,ASO治疗在临床前模型中预防NASH和肝纤维化, supporting PSD3 as a 基因tically validated target for future NASH therapy.6

Targeting novel biology using nucleotide therapeutics

As we uncover novel disease targets, 澳门第一赌城在线娱乐的化学家和生物化学家正在利用新技术来创造下一代疗法——超越传统的小分子, monoclonal antibodies and peptides. Nucleotide-based therapeutics 利用新型肝脏靶向反义寡核苷酸(ASOs)选择性地破坏这些变异诱导的蛋白质表达。.

Through a collaboration with Ionis Pharmaceuticals, we are investigating how ASOs may downregulate the harmful PNPLA3 variant with the aim of restoring fat break down in the liver, or to mimic the protective effects of the LoF mutation in the HSD17B13 基因.

Having reported the first preclinical evidence that PNPLA3 ASO therapy improved multiple stages of NASH, including lipid accumulation, 炎症和纤维化, and suppressed expression of the PNPLA3 148 蛋白质,7 the next step is to investigate the same approach in clinical studies. 在第二个项目中,澳门第一赌城在线娱乐正在探索ASO疗法治疗患者的潜力 HSD17B13 保护性变异, 在人类基因研究中, have been shown to rather protect against more advanced forms of liver disease, including HCC and liver-related mortality, 但不是脂肪变性.4,9 因此, by mimicking the protective HSD17B13 LoF mechanism, it may be possible to prevent disease progression or even reduce liver damage.

To optimise this 精密医学 approach, 澳门第一赌城在线娱乐必须在需要ASOs的相关肝细胞中传递它们. 澳门第一赌城在线娱乐的 ASOs are therefore attached to N-acetylgalactosamine (GalNAc), 一种糖分子,它被肝细胞上的受体识别,并迅速与它的ASO货物一起被细胞吸收. 这种选择性摄取旨在以正确的剂量和正确的位置提供治疗,以最大限度地减少副作用.

The search for non-invasive NASH diagnostics

Liver biopsy is currently used to confirm NASH diagnosis but is invasive, 有出血的危险, 昂贵且不适合持续监测疾病进展. 因此,澳门第一赌城在线娱乐支持研究,以确定非侵入性诊断生物标记物,用于澳门第一赌城在线娱乐的临床试验和, 随后, 临床实践中. We are active in both the academia-industry research consortia 石蕊 在欧洲和 灵活的 在美国, 旨在开发并强有力地验证NASH的潜在血液和成像生物标志物.

澳门第一赌城在线娱乐的科学家还与纽卡斯尔大学的领先学术和商业伙伴合作, UK, 纳什维尔生物科学, 美国, and the University of Hong Kong, to conduct whole genome sequencing in cohorts of patients with NASH.  他们正在研究纤维化和疾病进展的遗传驱动因素,以更好地了解疾病的生物学特性, and identify potential new targets and biomarkers for 精密医学. 通过这些合作和澳门第一赌城在线娱乐的临床试验项目,澳门第一赌城在线娱乐将分析来自不同人群的DNA和临床数据,以获得新的见解,澳门第一赌城在线娱乐希望这将使澳门第一赌城在线娱乐更接近准确, patient-friendly diagnostics.

不到10年, 澳门第一赌城在线娱乐希望证明精准医疗方法可以为NASH患者提供显著的益处. 澳门第一赌城在线娱乐需要证明,这些患者NASH组织学评估的改善可以转化为对诸如HCC和死亡率等硬性结果的有益影响. 澳门第一赌城在线娱乐还需要更好地理解PNPLA3中变异的作用机制, HSD17B13 and PSD3 and other 基因s implicated in NASH, and how they interact and may be targeted by combination treatment. 对于NASH研究来说,这是一个令人兴奋的时刻,澳门第一赌城在线娱乐对已经取得的成就感到非常鼓舞.




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  2. Carlsson B, Lindén D, Brolén G, 等. 回顾文章:遗传学在非酒精性脂肪性肝炎患者精准医疗中的新兴作用. 食品药物学. 2020;51(12):1305-1320.
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Veeva ID: Z4-49898
Date of preparation: February 2023