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Being able to precisely target the underlying molecular cause of an individual’s disease in heart failure would be a fundamental change from current clinical management paradigms which rely mainly on clinical signs and symptoms. A growing understanding of the genetic drivers of heart failure is laying the foundations for 精密医学 这是一种高度异质性的疾病，影响全世界6400万人.1
At AstraZeneca, we are collaborating with world-leading experts to identify novel targets and biomarkers to discover and develop 精密医学 in life-threatening diseases of the heart muscle, such as ischaemic cardiomyopathy (ICM) and idiopathic dilated cardiomyopathy (IDCM) and the inherited muscle wasting condition, 杜氏肌营养不良(DMD).
识别心力衰竭的分子指纹
通过利用人工智能和组学分析的力量, 澳门第一赌城在线娱乐的目标是揭开复杂的疾病生物学 heart failure 在个体患者的分子水平上. We are using machine learning to analyse large quantities of gene expression data from cardiac biopsy samples and stratify patients with heart failure into novel molecular sub-classes, 不管他们的临床症状和体征如何. These insights have revealed that the ‘molecular fingerprints’ shared by patients in these homogeneous sub-classes are unrelated to the ICM and IDCM classification generally used in heart failure diagnosis. We are starting to link sub-class-specific gene expression profiles to dysregulated molecular pathways and processes indicative of distinct disease biology across the different sub-classes. 澳门第一赌城在线娱乐还使用了过去试验中的基因表达数据, 与临床数据关联, 看看它们是否符合临床意义上的表型. 利用这些新信息, we plan to identify novel therapeutic targets that will form the basis of a 精密医学 approach to the care of patients with different molecular sub-classes of heart failure.
针对受损的心肌收缩
Among the genetic drivers of the stretched and weakened heart muscle seen in dilated cardiomyopathy (DCM) is a mutation in the gene for phospholamban (PLN), 细胞钙调节的关键蛋白质. Excessive PLN activity is linked to faulty calcium cycling and impaired heart muscle contraction and relaxation. 同时也是药物发现的关键目标, 到目前为止，这种蛋白质的结构已经被证明很难用常规药物靶向.
令人鼓舞的实验室数据已经证明了 反义寡核苷酸 (ASOs)在DCM中针对PLN活动.2 The research, carried out in collaboration with Ionis Pharmaceuticals and international heart failure scientists at University Medical Center Groningen and Karolinska Institute, shows that ASOs – strands of synthetic DNA – can be used to deplete the formation of PLN linked to DCM.
在临床前模型中编码 PLN R14 gene deletion, we used ASOs to reduce PLN activity, prevent cardiac dysfunction and improve survival.2 澳门第一赌城在线娱乐在其他心力衰竭模型中也看到了令人鼓舞的结果, making it a promising 精密医学 approach in cardiomyopathy and possibly other forms of heart failure.
DMD中的基因编辑
Advances in the care of children born with DMD have improved the outlook for those living with the disease, but progressive wasting of heart muscle can lead to life-limiting DCM and heart failure when individuals reach their 20s.
针对心肌的基因治疗进展有限.3 然而，使用澳门第一赌城在线娱乐完善的 CRISPR-Cas9基因编辑专业知识, 澳门第一赌城在线娱乐的团队正在研究如何去除肌营养不良蛋白基因中的错误序列, and using adeno-associated viruses to efficiently deliver targeted treatment into heart muscle cells. If this works, there is also the potential to extend this approach to other inherited diseases.
从心力衰竭的罕见基因驱动因素中学习
Through in-depth research into genetic drivers of heart failure we aim to advance understanding of why some patients with gene mutations develop the disease while others don’t.
在最近的一次合作中, scientists at our Centre for Genomics research identified an increased frequency of rare variants in the cardiomyopathy gene, TTN在5000名心力衰竭患者中，与超过13000名健康人相比.4 In addition, 在与心肌病相关的21种不同基因中发现了变异, irrespective of whether patients had heart failure with preserved or reduced ejection fraction – the main clinical categories of the disease. This means that, 尽管病人可能会有不同的症状去看医生, 他们潜在的基因驱动因素可能是相似的, 环境和合并症的作用比之前认为的要大.
对的病人，对的药物，对的时间
通过探索微妙的基因突变, variations in gene expression and gene-environment interactions in more common forms of heart failure, there is a potential to stratify patients for clinical trials of biomarker-guided targeted treatment. 借鉴临床试验设计的创新, and utilising an expanding toolkit of novel drug modalities we are aiming to target almost any type of underlying disease biology in heart failure so the right drug is available for the right patient at the right time.
