写的:
巴德Zarrouki
高级主管，生物科学代谢，CVRM，澳门第一赌城在线娱乐R&D、澳门在线赌城娱乐
马赛厄斯Liljeblad
副首席科学家, 翻译科学与实验医学, CVRM, 澳门第一赌城在线娱乐R&D、澳门在线赌城娱乐
非酒精性脂肪肝炎 (NASH) is a leading cause of liver disease around the world and numbers are expected to rise. NASH有显著的未满足的医疗需求，没有批准的药物. The emerging understanding of NASH biology and potential new 基因tically-validated drug targets hold the promise of providing patients with effective treatments.
NASH是一种慢性, 进行性肝病，脂肪在肝细胞中积聚(脂肪变性)。, 引起炎症和损伤. This can result in scar tissue (纤维化) and liver damage which may ultimately require a transplant.1 进行性NASH也可导致肝癌 肝细胞癌 (HCC)，甚至死亡.1 Diagnostic difficulties and a lack of understanding of the mechanisms of NASH have meant that treatment options are limited.
Fortunately, that appears to be changing and 精密医学 is anticipated to play a key role.2 澳门第一赌城在线娱乐的 精密医学 方法-瞄准正确的病人, 使用正确的药物旨在改善NASH患者的预后.
组学技术, 比如大规模基因组学, 是否能够识别新的致病基因变异. 事实上, 研究表明，在PNPLA3基因中, a single nucleotide substitution severely impairs normal fat breakdown in liver cells and dramatically increases the risk of developing all NAFLD hallmarks, 患HCC的风险高达10倍.3 另一个例子是HSD17B13基因, where a single nucleotide substitution leading to loss-of-function (LoF) of this enzyme, 对NASH有保护作用, 纤维化, 肝硬化, HCC和肝脏相关死亡率.4,5
了解更多澳门第一赌城在线娱乐想要的目标 PNPLA3 在下面的视频中，基因作为一种潜在的精准药物:
利用核苷酸疗法靶向新的生物学
当澳门第一赌城在线娱乐发现新的疾病目标时, our chemists and biochemists are leveraging new technologies to create the next 基因ration of therapeutics – going beyond traditional small molecules, 单克隆抗体和多肽. Nucleotide-based疗法 offer the advantage of being able to selectively disrupt protein expression induced by these variants using novel liver-targeted antisense oligonucleotides (ASOs).
通过与Ionis制药公司的合作, 澳门第一赌城在线娱乐正在调查ASOs是如何下调有害物质的 PNPLA3 旨在恢复肝脏中脂肪分解的变体, 或者模仿LoF突变的保护作用 HSD17B13 基因.
报告了第一个临床前证据 PNPLA3 ASO治疗可改善NASH的多个阶段, 包括脂质积累, 炎症和纤维化, 和抑制的表达式 PNPLA3 148 蛋白质,7 下一步是在临床研究中研究同样的方法. In a second programme, we are exploring the potential of ASO therapy to treat patients without the HSD17B13 保护性变异, 在人类基因研究中, 能预防更严重的肝脏疾病吗, 包括HCC和肝脏相关死亡率, 但不是脂肪变性.4,9 因此, 通过模拟保护性HSD17B13的LoF机制, 它有可能预防疾病进展，甚至减少肝损伤.
优化这种精准医疗方法, it is essential that we deliver ASOs in the relevant liver cells where they are needed. 因此，澳门第一赌城在线娱乐的ASOs与n -乙酰半乳糖胺(GalNAc)相连。, a sugar molecule that is recognised by receptors on hepatocytes and rapidly taken up inside the cells along with its ASO cargo. This selective uptake is designed to deliver treatment at the right dose and in the right place in order to minimise side effects.
寻找非侵入性NASH诊断方法
肝活检目前用于确诊NASH，但具有侵入性, 有出血的风险, is expensive and is not well suited to ongoing monitoring of disease progression. We are therefore supporting research to identify non-invasive diagnostic biomarkers for use in our clinical trials and, 随后, 临床实践中. 澳门第一赌城在线娱乐在学术界和产业界的研究联盟中都很活跃 石蕊 在欧洲和 灵活的 在美国, which aim to develop and robustly validate potential blood and imaging biomarkers for NASH.
澳门第一赌城在线娱乐的 scientists are also collaborating with leading academic and commercial partners at the University of Newcastle, UK, 纳什维尔生物科学, 美国, 以及香港大学, 对NASH患者进行全基因组测序. They are investigating the 基因tic drivers of 纤维化 and disease progression to better understand the biology of the disease, 并确定精准医疗的潜在新靶点和生物标志物. Through these collaborations and our clinical trial programmes we will analyse DNA and clinical data from diverse populations to gain new insights that we hope will take us closer to accurate, 便于患者使用诊断.
在不到十年的时间里, we hope to demonstrate that the 精密医学 approach can provide significant benefit for patients with NASH. We need to show that improvements in histological assessments of NASH in these patients translate into beneficial effects on hard outcomes such as HCC and mortality. We also need a better understanding of the mechanisms of action of the variants in PNPLA3, HSD17B13和PSD3以及其他与NASH相关的基因, 以及它们如何相互作用以及联合治疗的目标. It’s an exciting time for NASH research and we are very encouraged by what we have already achieved.
