Sci Transl Med:冷泉港实验室华人科学家发现改善骨髓增生异常综合症新疗法

2019-10-07 纪艳青 生物探索

骨髓增生异常综合症(MDS)是最常见的血液癌症之一,几乎没有治疗选择。现在,冷泉港实验室(CSHL)的研究人员发现了一种针对这种致命疾病的新的有希望的

骨髓增生异常综合症(MDS)是最常见的血液癌症之一,几乎没有治疗选择。现在,冷泉港实验室(CSHL)的研究人员发现了一种针对这种致命疾病的新的有希望的药物靶标。

CSHL研究员和癌症研究人员张凌波说:“目前,只有一小部分患者从MDS的标准疗法中受益。因此,对这种疾病的新疗法临床需求极为迫切。”

张凌波的实验室与斯隆·凯特琳纪念癌症中心和美国糖尿病消化与肾脏病研究所的专家合作发现了可以满足这一需求的新药物。他们的研究最近发表在《Science Translational Medicine》上。

张凌波说:“我们一直在与一个由医生和药物化学家组成的多学科团队合作,将我们的基本发现转化为新颖的疗法,可以在临床试验中对其进行测试,以使患者受益。我们的最终目标是创造一种能充分恢复对现有疗法有抵抗力的MDS患者血细胞生成的药物。”

要确切了解新药目标的工作原理,首先要知道为什么MDS如此难以治疗。与许多其他癌症不同,MDS的特征不是肿瘤。相反,这种血液癌有时被称为“骨髓衰竭疾病”。

骨髓的功能是为日常生存提供足够的血液。当血细胞因出血而流失或年龄过大而无法工作时,就会产生替代细胞并催熟红细胞。但能这些替换产生的MDS太少,有缺陷或两者兼而有之。

MDS症状(如贫血)的传统治疗选择依赖于人体产生更成熟的红细胞的自然能力,这是由促红细胞生成素(EPO)激素驱动的。

骨髓中发育的未成熟红细胞(称为祖细胞)必须暴露于EPO中,才能触发它们的最终变化,使其转变为可完全成熟的完全成熟红细胞,以帮助人体。这样一来,向骨髓中注入大量促红细胞生成素就可以解决大多数MDS病例,然而事实并非如此。

之所以只有一小部分患者对基于EPO的常规治疗有反应,是因为许多MDS患者的骨髓中没有足够的功能性祖细胞。在某些情况下,可用的功能性细胞确实会变成成熟的红细胞。但是,一旦供应耗尽,EPO治疗就会停止工作,从而导致耐药性。这就是张凌波和他的同事决定采用不同方法的原因。

张凌波解释说:“因此,要治疗它,不能靶向已故的祖细胞。它们制造新细胞的能力非常有限。但是对于较早的细胞,我们有机会。”

他们不依赖EPO及其靶祖细胞,而是选择靶向更年轻的祖细胞。研究人员发现,当这些细胞有缺陷时,激活称为CHRM4的特定蛋白质受体会极大地阻碍其分裂为这些至关重要的EPO反应性祖细胞的能力。通过阻断该受体,张凌波及其同事可以恢复健康的血细胞生成。

在通过基因设计来反映人类MDS病理特征的小鼠中,这种策略显著提高了存活率。

“更重要的是,这些临床前测试表明,该疗法具有持续和长期的治疗效果,”张凌波说。“我们现在正在将这一发现转化为临床发展,我们希望我们的进展将在不久的将来造福患者。”

原始出处:

Gaurang Trivedi, et al. Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors. Science Translational Medicine. 25 Sep 2019


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    2019-10-09 kcb074
  8. 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