Stratified adaptive therapeutic studies in pulmonary arterial hypertension caused by mutations in BMPR2

BMPR2突变所致肺动脉高压的分层适应性治疗研究

• 批准号: MR/T025646/1
• 负责人: Mark Toshner
• 金额: $ 220.54万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT025646%2F1
• 关键词: Stratified; adaptive; therapeutic; studies; pulmonary

Pulmonary arterial hypertension is a devastating life-limiting disease more likely to affect young women. Patients face daily symptoms, an early death and potentially lung transplantation. 1 in 4 patients has a genetic form of the disease. Treatments do not address the underlying genetic cause of the disease yet. We propose the first ever trial of treatments aimed at the genetic form of the disease, mutations in a protein called the bone morphogenetic type 2 receptor, using 2 drugs that have shown promise in improving function in cells taken from patients and in animal models; hydroxychloroquine and phenylbutyrate. We have only been able to do this because of previous investment by the MRC and British Heart Foundation in the world's biggest genetic studies in pulmonary arterial hypertension that have identified patients in the UK who might benefit from the treatments. The trial uses a new way of assigning drugs to patients-an adaptive design. As the trial progresses if either drug is showing a bigger effect, the trial will "adapt" to this new information by increasing the proportion of patients who get the drug. This will allow the team to test more than one drug at a time but concentrate on drugs that are having bigger effects. The trial will be available all across the UK running from all 7 of the nationally accredited pulmonary hypertension centres.

肺动脉高压是一种毁灭性的限制生命的疾病，更容易影响年轻女性。患者每天都会出现症状，可能会过早死亡，并可能进行肺移植。每4名患者中就有1人患有这种疾病的遗传形式。治疗还没有解决这种疾病的潜在遗传原因。我们提出了有史以来第一次针对这种疾病的基因形式的治疗试验，即一种叫做骨形态发生2型受体的蛋白质的突变，使用两种药物，这两种药物在改善取自患者和动物模型的细胞的功能方面显示出了希望；羟氯喹和苯基丁酸盐。我们之所以能够做到这一点，是因为MRC和英国心脏基金会之前对世界上最大的肺动脉高压基因研究的投资，这些研究已经确定了英国可能从治疗中受益的患者。这项试验采用了一种新的方法来给病人分配药物——适应性设计。随着试验的进行，如果任何一种药物显示出更大的效果，试验将通过增加服用该药物的患者比例来“适应”这一新的信息。这将允许该团队一次测试多种药物，但将重点放在效果更大的药物上。该试验将在全英国所有7家国家认可的肺动脉高压中心进行。