ORIGINALLY PUBLISHED
22 April 2022
Written by:
Daniel Lindén, PhD
Associate Prof, Senior Principal Scientist and Senior Director at Bioscience Metabolism, Research and Early CVRM, BioPharmaceuticals R&D, AstraZeneca
Stefano Romeo, MD, PhD
Prof. Senior Consultant, Principal Investigator, Sahlgrenska学院医学研究所分子和临床医学教授, University of Gothenburg, Sweden
疾病生物学认识的进步以及基因测序和数据分析的重大创新创造了一个高度肥沃的科学环境，支持在非酒精性脂肪性肝炎(NASH)遗传变异鉴定方面取得重大进展。.
Partnering to push the boundaries of science
澳门葡京赌博游戏已经合作了五年多，以确定和验证NASH的新治疗靶点, a chronic liver disease which can have serious, life-threatening consequences.
目前还没有批准的NASH治疗方法，澳门葡京赌博游戏相信通过靶向遗传因素(如PNPLA3)来改变这一现状的潜力很大，澳门葡京赌博游戏在2019年的《澳门葡京网赌游戏》杂志上报道了这一点, and HSD17β13, as well as PSD3 a variant that we reported in Nature Metabolism in 2022.1 We have examined these opportunities and others in a review in the Journal of Hepatology, which is part of their collection on therapeutic approaches in NASH.2
Understanding NASH
非酒精性脂肪性肝病(NAFLD)及其更严重的变异型NASH的病例呈上升趋势, but therapeutic options remain limited.3,4 肝脏中的脂肪堆积可导致慢性肝病，并可能引发危及生命的并发症, including cirrhosis and liver cancer, as well as obesity, type 2 diabetes, and chronic kidney disease.5
NASH是一种复杂的疾病，有多种驱动因素，包括强烈的遗传因素.3 澳门葡京赌博游戏的早期研究集中在确定基因靶点，以便为这种疾病开发量身定制的治疗方法.
许多与NASH相关的基因变异会影响肝脏的脂质代谢. Some variants, such as PNPLA3, contribute to NASH risk while others, such as HSD17β13, are protective. 这两种类型都可以为精确医学治疗的发展提供信息，从而抑制或复制它们的效果.
新的药物模式使特异性靶向NASH遗传变异的能力成为可能. For example, nucleotide therapies such as antisense oligonucleotides 提供一种减少疾病相关基因表达的方法，并且可以靶向递送到肝脏.
In combination with affordable companion diagnostic tests, 这些新方法可以根据患者的遗传特征为他们提供高效的新治疗方法. 澳门葡京赌博游戏设想NASH治疗的未来是基于一系列针对不同疾病驱动因素的药物，在诊断测试和精准医学框架的指导下，在正确的时间为正确的患者提供正确的治疗.
Watch our video to find out more about our work on PSD3
Turning science into medicine
The early R&D过程从选择正确的目标开始，这可以说是澳门葡京赌博游戏需要做出的最重要的决定之一.
Step 1: Target identification
In this first step, 澳门葡京赌博游戏集中研究了32个先前发现与循环甘油三酯相关的基因变异. 澳门葡京赌博游戏研究了这些基因变异与肝脏脂肪含量的关系,700 individuals in whom liver fat content was measured by magnetic spectroscopy. 这导致在该队列中鉴定出PSD3变异与肝脏脂肪含量降低之间的新关联.
Step 2: Target validation
These results were then validated in >1,900例肝活检样本来自欧洲肝病风险个体的肝活检队列. This was confirmed in two additional cohorts, in nearly 11,000 subjects from the UK Biobank and >670 at-risk obese subjects in an independent cohort. 澳门葡京赌博游戏发现PSD3的下调不仅与肝脏脂肪含量降低有关，而且与炎症和纤维化有关，这是脂肪肝患者的重要因素.
Step 3: Lead identification
在哥德堡大学和Ionis制药公司合作，澳门葡京赌博游戏展示了广泛的概念验证 in vitro and in vivo 小干扰RNA (siRNA)和反义寡核苷酸(ASOs)检测. We have shown that in primary human hepatocytes cultured in 3D organoids, PSD3 silencing reduced intracellular fat accumulation. Furthermore, 用肝脏靶向PSD3 ASO治疗饮食性NASH临床前模型, reduced liver fat content, inflammation and fibrosis.
Looking to the future
Further studies are needed to fully understand the mechanism of action, 但澳门葡京赌博游戏的研究结果可能会导致针对PSD3基因的新疗法，以保护患者免受肝脏脂肪过度积累和FLD的进展, including NASH. 澳门葡京赌博游戏期待着继续合作，利用基因组学的力量为患者开发有针对性的治疗方法.
