MICA: Identification of compounds capable of de-repressing zeta-globin in order to treat patients with severe alpha-thalassaemia

MICA：鉴定能够解除 zeta 珠蛋白抑制的化合物，以治疗严重 α 地中海贫血患者

基本信息

批准号：
MC_EX_MR/R023301/1
负责人：
Douglas Higgs
金额：
$ 1.14万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MC_EX_MR%2FR023301%2F1
关键词：
MICA Identification compounds capable de

项目摘要

Haemoglobin (Hb) is the major component of the protein found in red blood cells, it gives blood its red colour and is responsible for carrying oxygen around the body. Haemoglobin is made up of four chains: 2 alpha chains and 2 beta chains. Mutations in the genetic code (the DNA) responsible for producing these chains can lead to decreased production of the alpha chains, a condition called alpha-thalassaemia (mutation of the beta-chains, causes beta-thalassemia). There are four alpha-globin genes in humans, each of which normally contributes to alpha-globin production. If one or two genes are affected by mutations, then this produces a mild anaemia without any symptoms. However, if three alpha-globin genes are affected, this can lead to a severe anaemia needing regular transfusions. If all four alpha-globin genes are affected, this means that no functional haemoglobin can be produced, and such patients die in the womb approximately 4-6 months after conception (a condition called Barts Hydrops fetalis). Mild alpha-thalassaemia provides some protection against the infectious disease malaria. In certain parts of the world, alpha-thalassaemia is therefore very common: the carrier frequency is 4-8% in Southern China and Hong Kong and at a similar level in the Thai, Filipino and Vietnamese populations, however, it is most common in Northern Thailand where up to 14% of the population are carriers. Severe alpha-thalassemia is therefore a major global health problem with at least 26,000 at-risk pregnancies annually and because of migration this is now a global health problem. At the moment, treatments for alpha-thalassaemia are limited to blood transfusion and occasionally, bone marrow transplantation. Bone marrow transplantation can be very dangerous, with up to 1/5 patients dying because of the procedure itself. Regular blood transfusions also cause serious medical problems long-term. In addition, it is normally recommended that Bart's Hydrops fetalis babies are aborted because they are so unwell prior to being born. We therefore urgently need new treatments for severe forms of alpha-thalssaemia. When babies develop, they initially produce a different globin chain, similar to alpha-globin for the first 8 weeks after conception; this is called zeta-globin. We know this is capable of substituting for alpha-globin in adults. Unfortunately however, it is normally switched off after eight weeks. If we could find a way of turning it back on in adult red blood cells, this would treat patients with severe forms of alpha-thalssaemia and could allow them to live a normal life.In this project, we aim to identify chemical compounds which could be used as medicines to switch zeta-globin back on, thereby treating patients with severe alpha-thalassaemia. To help undertake this, we have made a mouse, where zeta-globin is "tagged" by a fluorescent protein. This means that we have a sensitive and specific way of identifying blood cells where zeta-globin is turned on, as when zeta-globin is on, the red blood cell glows. This allows us to add lots of different compounds to red blood cells from the mouse, and see quickly and easily which ones cause the red blood cells to glow. Once we have identified potential compounds, we will make sure they also turn zeta-globin back on in human cells and try and understand how they are turning zeta-globin back on by doing additional experiments. We will perform the initial screen of compounds by collaborating with a pharmaceutical company called AstraZeneca, as they have particular expertise in developing medicines. Longer-term, we would aim to test the compounds, initially in mouse models of alpha-thalassaemia, then in human cellular systems and if that is successful, in people.

血红蛋白（HB）是在红细胞中发现的蛋白质的主要组成部分，它赋予血红色，并负责在体内携带氧气。血红蛋白由四个链组成：2条α链和2条β链。负责产生这些链的遗传密码（DNA）中的突变会导致α链的产生降低，α链的产生，这种疾病称为α-thalassasasasa-链球菌（β-链的突变，会导致β-核阿无血症）。人类中有四个α-珠蛋白基因，它们通常有助于α-珠蛋白产生。如果一个或两个基因受突变的影响，则会产生轻度的贫血而没有任何症状。但是，如果三个α-珠蛋白基因受到影响，则可能导致严重的贫血需要常规输血。如果所有四个α-珠蛋白基因都受到影响，这意味着无法产生功能性血红蛋白，并且此类患者在受孕后约4-6个月死亡（一种称为Barts Hydrops Fetalis）。轻度的α-甲状腺肿性可保护感染性疾病疟疾。因此，在世界某些地区，α-甲性贫乏是非常普遍的：在中国南部和香港，携带者的频率为4-8％，在泰国，菲律宾人和越南人口的水平相似，但是，在泰国北部，最常见的是，多达14％的人口是携带者。因此，严重的α-甲性疾病是一个主要的全球健康问题，每年至少有26,000次处于危险的怀孕，并且由于迁移，这现在是一个全球健康问题。目前，α-甲性贫血的治疗仅限于输血，有时是骨髓移植。骨髓移植可能非常危险，由于该手术本身，多达1/5例患者死亡。常规输血也会长期导致严重的医疗问题。此外，通常建议BART的Harrops胎儿婴儿流产，因为它们在出生之前是如此不适。因此，我们迫切需要针对严重形式的α-thalssamia的新治疗方法。当婴儿发育时，他们最初产生不同的球蛋白链，类似于受孕后的头8周。这称为Zeta-Globin。我们知道这能够在成年人中代替α-珠蛋白。但是不幸的是，通常在八周后关闭它。如果我们能找到一种在成年红细胞中重新打开的方法，这将治疗患有严重形式的α-thal- thalssaemia的患者，并可以使他们过着正常的生活。在这个项目中，我们旨在识别可以用作药物来将Zeta-Globin用作药物，从而将Zeta-Globin重新切换回患有严重的Alpha-Alpha-thallassaemia。为了帮助实现这一目标，我们制作了一只小鼠，其中Zeta-Globin被荧光蛋白“标记”。这意味着我们有一种敏感且特定的方式来识别Zeta-Globin被打开的血细胞，就像Zeta-Globin时一样，红细胞发光。这使我们能够从小鼠的红细胞中添加许多不同的化合物，并快速，轻松地看到哪些化合物会导致红细胞发光。一旦确定了潜在化合物，我们将确保它们还会在人类细胞中重新启动Zeta-Globin，并尝试通过进行其他实验来理解它们如何重新启动Zeta-Globin。我们将通过与一家名为Astrazeneca的制药公司合作，在开发药物方面具有特殊的专业知识，从而执行化合物的初始屏幕。从长远来看，我们将旨在测试化合物，最初是在α-甲状腺肿的小鼠模型中，然后在人类细胞系统中，如果成功的话。