精准医学和基因验证靶点揭示了NASH治疗的新机遇

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非酒精性脂肪性肝炎(NASH)是世界范围内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望为患者提供有效的治疗.

NASH是一种慢性, 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)和肝脏损伤，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选择有限.

幸运的是，这种情况似乎正在改变，精准医疗有望发挥关键作用.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.³ An other example is for the the HSD17B13 基因, 单核苷酸取代导致这种酶的功能丧失(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对NASH和肝纤维化有保护作用, 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创造新一代的治疗方法——超越传统的小分子, monoclonal antibodies and peptides. Nucleotide-based therapeutics 提供的优势是能够使用新的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. 在第二个节目中，澳门第一赌城在线娱乐正在探索ASO治疗的潜力，以治疗患者没有 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的相关肝细胞中提供aso. 澳门第一赌城在线娱乐的 ASOs are therefore attached to N-acetylgalactosamine (GalNAc), 这是一种糖分子，可以被肝细胞上的受体识别，并与ASO货物一起迅速被细胞吸收. 这种选择性摄取的目的是在正确的地方以正确的剂量提供治疗，以尽量减少副作用.

The search for non-invasive NASH diagnostics

Liver biopsy is currently used to confirm NASH diagnosis but is invasive, carries a risk of bleeding, 是否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在临床试验中使用非侵入性诊断生物标志物的研究, 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, 旨在开发和验证NASH潜在的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，以更好地了解该疾病的生物学, 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.

在不到十年的时间里, 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，在这些患者中，NASH组织学评估的改善转化为对HCC和死亡率等硬结果的有益影响. 澳门第一赌城在线娱乐还需要更好地了解PNPLA3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，这是一个激动人心的时刻，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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