Developing stem cell therapies for the treatment of inherited and acquired liver disease

开发干细胞疗法来治疗遗传性和获得性肝病

• 批准号: MR/K008781/1
• 负责人: Jon Frampton
• 金额: $ 7.82万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK008781%2F1
• 关键词: Developing; stem; cell; therapies; treatment

Stem cell based approaches are likely to be key in the future development of novel therapies for many diseases ranging from the replacement or repair of organs affected by injury or the effects of ageing through to ways to modify the body's own responses to injury, which can have lasting damaging effects when out of control. This project will underpin a research initiative between the University of Birmingham (UoB) and the Guangzhou Institute of Biomedicine and Health (GIBH) that seeks to develop novel stem cell based therapies. GIBH has a strong international reputation in fundamental stem cell biology, while UoB has unrivalled experience in the development of cell-based therapies and their testing in clinical trials. This initiative will be a model for international research collaboration at the highest level, each institution gaining from the other's expertise and specialist resources to enable delivery of cutting-edge research outcomes with the objective to translate discoveries rapidly into patient benefit. This pilot project will focus on the development of stem cell-based means to tackle a wide range of liver diseases. Liver disease is a major cause of morbidity and mortality in modern societies. In the UK the prevalence of chronic liver disease is between 0.76-1% and represents the fifth 'big killer' in England & Wales, and is the only disease in the top 5 that is still increasing year-on-year. The majority of this relates to chronic liver damage due to alcohol, viruses or obesity, but also includes liver damage resulting from acute (paracetamol) injury or autoimmune destruction. The situation of liver disease is even more alarming in China. Historically this reflected Hepatitis B infection, although chronic liver disease due to obesity is now rising. In addition, a number of inherited traits impact on liver function resulting in metabolic disorders. For many of these diseases there is no effective treatment, except liver transplantation.The project will explore how induced pluripotent stem cells (iPSCs) can be utilised in a variety of ways in the treatment of liver diseases. iPSCs can be made from any readily available cells, such as from the skin, and have the potential to be maintained and expanded indefinitely. At the same time iPSCs can be converted into cell types to act as replacements for damaged tissue or into specific cell types with other useful therapeutic properties. GIBH are world leaders in the generation of iPSCs, and will join forces with the UoB team to produce and test two different cell types from them that have relevance in the treatment of liver disease. The first will be liver cells (hepatocytes), which the Birmingham team has expertise in producing f(from human embryonic stem cells) and testing in animal models of liver damage. The second cell type are mesenchymal stromal (or stem) cells (MSCs), which have the ability to dampen the body's own exaggerated inflammatory response to certain injuries, which if left unchecked can itself result in long term damage.In addition to setting up and sharing protocols for the generation and testing of hepatocytes and MSCs, this project will also lay the groundwork for the establishment of a shared cell 'bank' that will pave the way for more extensive research. In particular, it will act as a resource for a more 'personalised' approach to stem cell-based therapy since iPSCs will be made from a wide range of individuals with different genetic backgrounds, including some who have defined inherited genetic defects that impact upon liver function.Overall, the proposed project will contribute to the foundation for a joint research laboratory and a stem cell bank between the involved institutions of Birmingham and Guangzhou, and is expected to develop new concepts and therapeutic possibilities that will benefit people from the UK and China.

基于干细胞的方法可能是未来开发许多疾病新疗法的关键，这些疾病包括替换或修复受损伤或衰老影响的器官，以及改变人体自身对损伤的反应，当损伤失控时，可能会产生持久的破坏性影响。该项目将支持伯明翰大学 (UoB) 和广州生物医学与健康研究院 (GIBH) 之间的一项研究计划，旨在开发基于干细胞的新型疗法。 GIBH 在基础干细胞生物学领域享有盛誉，而 UoB 在细胞疗法开发及其临床试验测试方面拥有无与伦比的经验。该举措将成为最高水平的国际研究合作的典范，每个机构都可以从对方的专业知识和专业资源中获益，从而能够提供尖端的研究成果，以期将发现迅速转化为患者的利益。该试点项目将重点开发基于干细胞的方法来治疗多种肝脏疾病。肝病是现代社会发病和死亡的主要原因。在英国，慢性肝病的患病率在0.76-1%之间，是英格兰和威尔士的第五大“杀手”，也是前五名中唯一仍在逐年增加的疾病。其中大部分与酒精、病毒或肥胖引起的慢性肝损伤有关，但也包括急性（扑热息痛）损伤或自身免疫破坏引起的肝损伤。在中国，肝病的情况更加令人担忧。从历史上看，这反映了乙型肝炎感染，尽管肥胖引起的慢性肝病现在正在增加。此外，许多遗传特征会影响肝功能，导致代谢紊乱。对于其中许多疾病，除了肝移植外，没有有效的治疗方法。该项目将探索如何以多种方式利用诱导多能干细胞（iPSC）来治疗肝脏疾病。 iPSC 可以由任何容易获得的细胞（例如皮肤细胞）制成，并且具有无限维持和扩展的潜力。同时，iPSC 可以转化为细胞类型，作为受损组织的替代品，或转化为具有其他有用治疗特性的特定细胞类型。 GIBH 是 iPSC 生成领域的世界领先者，并将与 UoB 团队联手生产和测试两种与肝病治疗相关的不同细胞类型。第一个是肝细胞（肝细胞），伯明翰团队拥有利用人类胚胎干细胞生产肝细胞和在肝损伤动物模型中进行测试的专业知识。第二种细胞类型是间充质基质（或干）细胞（MSC），它能够抑制人体自身对某些损伤的过度炎症反应，如果不加以控制，这种炎症反应本身就会导致长期损伤。除了建立和共享肝细胞和 MSC 的生成和测试协议之外，该项目还将为建立共享细胞“库”奠定基础，从而铺平道路。 进行更广泛的研究。特别是，它将作为一种更加“个性化”的干细胞治疗方法的资源，因为 iPSC 将由具有不同遗传背景的广泛个体制成，其中包括一些已明确影响肝功能的遗传性遗传缺陷的人。总体而言，拟议的项目将为伯明翰和广州相关机构之间建立联合研究实验室和干细胞库做出贡献，预计将开发新的概念和治疗方法。 这将使英国和中国人民受益。

项目成果

Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.

富马酰乙酰乙酸水解酶敲除兔遗传性酪氨酸血症1型模型

• DOI: 10.1074/jbc.m116.764787
• 发表时间: 2017-03-17
• 期刊: The Journal of biological chemistry
• 作者: Li L;Zhang Q;Yang H;Zou Q;Lai C;Jiang F;Zhao P;Luo Z;Yang J;Chen Q;Wang Y;Newsome PN;Frampton J;Maxwell PH;Li W;Chen S;Wang D;Siu TS;Tam S;Tse HF;Qin B;Bao X;Esteban MA;Lai L
• 通讯作者: Lai L

Generation of knockout rabbits using transcription activator-like effector nucleases.

• DOI: 10.1186/2045-9769-3-3
• 发表时间: 2014
• 期刊: Cell regeneration (London, England)
• 作者: Wang Y;Fan N;Song J;Zhong J;Guo X;Tian W;Zhang Q;Cui F;Li L;Newsome PN;Frampton J;Esteban MA;Lai L
• 通讯作者: Lai L