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Precision genome editing with tandem autologous transplantation as a therapy for multiple severe immune-mediated diseases

精准基因组编辑与串联自体移植治疗多种严重免疫介导疾病

基本信息

批准号：
MR/T030410/1
负责人：
Calliope Athina Dendrou
金额：
$ 33.24万
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：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT030410%2F1
关键词：
Precision genome editing tandem autologous

项目摘要

Autologous haemopoietic stem cell transplantation (ASCT) is emerging as an important therapy for patients with severe immune-meditated diseases (IMDs). Recent studies have shown that it is safe and effective for treating severe IMDs such as multiple sclerosis (MS) and scleroderma. This involves collecting bone marrow derived stem cells from a patient and then eliciting severe but transient immunosuppression using a combination of chemotherapy and therapeutic antibodies. This eradicates a large portion of the immune system including the autoreactive cells. Bone marrow derived stem cells are then reinfused and the immune system is reconstituted afresh with minimal long-term side effects. European Bone Marrow Transplant registry data show that more than 2500 patients have had autologous transplants for IMDs. Only one death has occurred since 2005 following autologous transplantation for MS. ASCT is superior to all other therapies in MS for inducing long-term remissions and it is the only treatment that has been found to reduce disability. In scleroderma, ASCT results in a very marked improvement in survival (86% v 51% at 6 years). Although ASCT can halt disease progression for many patients, 30-50% eventually re-develop their original IMD and 5-10% develop a different IMD. There is therefore significant scope to improve this therapeutic strategy. In recent years there has been a revolution in molecular biology due to programmable nucleases such as CRISPR-Cas9 because they allow us to make precise changes to the sequence of the genome. They are likely to become hugely important therapeutic tools within the next decade. We are using this technology to modify the genome sequence in bone marrow derived stem cells for curing inherited disorders of blood cell production and the immune system. The next step is to use this approach to treat acquired disorders of the immune system such as IMDs. Large-scale genetic analyses have revealed a target gene that is broadly protective across 20 different IMDs including multiple sclerosis (MS), scleroderma, rheumatoid arthritis and Crohn's disease. For these diseases there is around a 10- fold risk reduction; meaning that 9 in 10 patients would not have developed the disease had they had two copies of the protective variant. The protective variant does not result in increased risk for malignancy and does not lead to immunodeficiency. We will develop a strategy that allows us to change the genetic sequence of bone marrow-derived stem cells to mimic the protective genetic variants identified by large-scale genetic studies. These edited cells could then be used to repopulate the immune system with genetically modified cells with a stem cell transplant. This approach would potentially eradicate the harmful immune cells and significantly and permanently reduce the chance of relapse. This is a completely novel approach for treating IMDs and it is potentially applicable to a broad range of different diseases. Through our editing strategy we will change the DNA sequence that defines the structure of the protein, to mimic the naturally occurring protective variants, which attenuate its function. This protein plays a critical role in immune cell activation and it will cleanly and precisely decrease the immune response. The editing strategy will be tested in an IMD mouse model, which mimics the pathology of MS, to determine if the edit protects against IMD development. We will also define what proportion of edited cells required for the protective effect by performing transplants in mice using mixtures of edited and normal cells.

自体造血干细胞移植（ASCT）正在成为严重免疫介导疾病（IMD）患者的重要治疗方法。最近的研究表明，它是安全和有效的治疗严重的IMD，如多发性硬化症（MS）和硬皮病。这涉及从患者收集骨髓来源的干细胞，然后使用化疗和治疗性抗体的组合引发严重但短暂的免疫抑制。这根除了免疫系统的很大一部分，包括自体反应细胞。然后重新输注骨髓来源的干细胞，重新重建免疫系统，长期副作用最小。欧洲骨髓移植登记数据显示，超过2500例患者接受了自体移植治疗IMD。自2005年以来，MS自体移植后仅发生一例死亡。ASCT在诱导MS长期缓解方面上级所有其他疗法，是唯一发现可减少残疾的治疗方法。在硬皮病中，ASCT导致生存率非常显著的改善（6年时86% vs51%）。尽管ASCT可以阻止许多患者的疾病进展，但30-50%的患者最终会重新发展他们原来的IMD，5-10%的患者会发展出不同的IMD。因此，有很大的空间来改善这种治疗策略。近年来，由于CRISPR-Cas9等可编程核酸酶的出现，分子生物学发生了一场革命，因为它们允许我们对基因组序列进行精确的改变。它们很可能在未来十年内成为非常重要的治疗工具。我们正在使用这项技术来修改骨髓源性干细胞的基因组序列，以治疗血细胞生成和免疫系统的遗传性疾病。下一步是使用这种方法来治疗免疫系统的获得性疾病，如IMD。大规模的遗传分析揭示了一种靶基因，它对20种不同的IMD具有广泛的保护作用，包括多发性硬化症（MS）、硬皮病、类风湿性关节炎和克罗恩病。对于这些疾病，风险降低了大约10倍;这意味着如果他们有两个保护性变体的拷贝，10个患者中有9个不会患上这种疾病。保护性变异不会导致恶性肿瘤风险增加，也不会导致免疫缺陷。我们将开发一种策略，使我们能够改变骨髓源性干细胞的遗传序列，以模仿大规模遗传研究所确定的保护性遗传变异。然后，这些编辑过的细胞可以通过干细胞移植用遗传修饰的细胞重新填充免疫系统。这种方法可能会消除有害的免疫细胞，并显着和永久地减少复发的机会。这是一种治疗IMD的全新方法，可能适用于各种不同的疾病。通过我们的编辑策略，我们将改变定义蛋白质结构的DNA序列，以模拟天然存在的保护性变体，从而减弱其功能。这种蛋白质在免疫细胞激活中起着关键作用，它会干净而精确地降低免疫反应。编辑策略将在IMD小鼠模型中进行测试，该模型模拟MS的病理学，以确定编辑是否防止IMD发展。我们还将通过使用编辑过的细胞和正常细胞的混合物在小鼠中进行移植来确定保护作用所需的编辑过的细胞的比例。