写的:
丹尼尔·林德康博士
助理教授, 高级首席科学家和生物科学代谢高级主管, 研究与早期CVRM, 澳门第一赌城在线娱乐R&D、澳门在线赌城娱乐
Stefano Romeo，医学博士，博士
Prof. 高级顾问, 首席研究员, Professor in Molecular and Clinical Medicine at the Institute of Medicine at the Sahlgrenska Academy, 哥德堡大学, Sweden
Advances in understanding of disease biology and major innovations in gene sequencing and data analysis has created a highly fertile scientific environment to support significant progress in the identification of genetic variants for non-alcoholic steatohepatitis (NASH).
合作推动科学的发展
We have been collaborating together for more than five years to identify and validate novel therapeutic targets for NASH, 这是一种慢性肝病，可能会有严重的, 致命的后果.
There are currently no approved treatments for NASH and we believe that there is great potential to change this by targeting genetic factors 例如PNPLA3 that we reported in Molecular Metabolism in 2019, 和HSD17β13, 以及澳门第一赌城在线娱乐在2022年的《澳门第一赌城在线娱乐》杂志上报道的PSD3变异.1 澳门第一赌城在线娱乐对这些机会和其他机会进行了审查 国际肝病杂志这是他们收集的NASH治疗方法的一部分.2
理解纳什
Cases of non-alcoholic fatty liver disease (NAFLD) and its more serious variant NASH are on the rise, 但治疗选择仍然有限.3,4 Fat accumulation in the liver can lead to chronic liver disease with potentially life-threatening complications, 包括肝硬化和肝癌, 还有肥胖, 2型糖尿病, 慢性肾脏疾病.5
NASH is a complex disease with multiple drivers, including strong genetic factors.3 Our early research has focused on identifying genetic targets in order to develop tailored therapies for this disease.
Many of the genetic variants linked to NASH affect lipid metabolism in the liver. 一些变种, 例如PNPLA3, 导致NASH风险的因素, 如HSD17β13, 是保护. Both types can inform the development of precision medicine treatments that either suppress or replicate their effects.
The ability to specifically target genetic variants in NASH is being enabled by new drug modalities. 例如, 核苷酸疗法，如反义寡核苷酸 provide a way to reduce the expression of disease-associated genes and can be targeted for delivery to the liver.
结合可负担的配套诊断测试, these new approaches could provide highly effective new treatments that are selected for patients based on their genetic characteristics. We envision a future for NASH therapies based on a range of drugs targeting different disease drivers that are guided by diagnostic tests and a precision medicine framework to offer the right treatment to the right patients at the right time.
观看澳门第一赌城在线娱乐的视频，了解更多关于澳门第一赌城在线娱乐在PSD3上的工作
将科学转化为医学
早期的R&D process starts with selecting the right target which is arguably one of the most important decisions we need to make.
步骤1:目标识别
在第一步中, we focused on 32 gene variants that had previously been found to be associated with circulating triglycerides. We investigated the association of these gene variants with liver fat content in over 2,用磁波谱法测量了700人的肝脏脂肪含量. This led to the identification of a novel association between the PSD3 variant and 降低肝脏脂肪含量 in this cohort.
步骤2:目标验证
These results were then validated in >1,900 liver biopsy samples from the Liver Biopsy Cohort in European individuals at risk of liver disease. 这在另外两个队列中得到证实, 将近11年,000 subjects from the UK Biobank and >670 at-risk obese subjects in an independent cohort. We found that downregulation of PSD3 was not only associated with 降低肝脏脂肪含量 but also 炎症和纤维化 which are important factors in patients with fatty liver disease.
步骤3:引线识别
At 哥德堡 University and in collaboration with Ionis Pharmaceuticals we have shown proof-of-concept with extensive 在体外 and in vivo testing using small interfering RNA (siRNA) and antisense oligonucleotides (ASOs). 澳门第一赌城在线娱乐已经证明，在3D类器官培养的原代人肝细胞中, PSD3沉默减少细胞内脂肪堆积. 此外, treating preclinical models with diet-induced NASH with a liver-targeted PSD3 ASO, 降低肝脏脂肪含量, 炎症和纤维化.
展望未来
需要进一步的研究来充分了解其作用机制, but our results could lead to new treatments that target the PSD3 gene to protect patients from excessive liver fat accumulation and progression of FLD, 包括纳什. We look forward to continuing our collaboration and using the power of genomics to develop targeted treatments for patients.
