Haemoglobinopathies as a target for Fetal Transplantation

血红蛋白病作为胎儿移植的目标

• 批准号: MR/V006797/1
• 负责人: Joseph Davidson
• 金额: $ 36.38万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FV006797%2F1
• 关键词: Haemoglobinopathies; target; Fetal; Transplantation

BackgroundOver 200 babies are born each year in the UK with inherited blood disorders such as haemoglobinopathies. These disorders affect the oxygen carrying part of the red blood cell. Thalassaemia is one of the most common. Treatment involves regular blood transfusions throughout the life of the patient. This can lead to multiple issues in later life including diabetes, heart conditions and thinning of the bone due to excess accumulation of iron in the tissues. Furthermore, many individuals require complex multi-disciplinary care and have considerable disruption to school and work due to hospital admissions and problems with symptoms. At present, Thalassaemia can be cured with a Bone Marrow Transplant. This involves giving donor stem cells, however this is not offered very often because there are significant risks involved. The immune system of the patient and the immune cells in the transplant can both cause significant problems, including death. There is also a considerable risk of Graft vs Host Disease, wherein the transplanted cells begin to attack the recipient. For that reason, there is a lot of research into the way that the immune systems function in this setting. Fetal Stem Cell TransplantThe immune system of the fetus is unique, because it is still learning what it needs to call a friend ("self-recognition" of "tolerance") or an enemy. Research has already shown that giving a transplant at this time can give tolerance to the transplant without needing to give any medication to suppress the immune system, avoiding many of the risks of post-natal bone marrow transplant. However we have not been able to use this to treat a model for haemaglobinopathies like thalassaemia.Our Research We know that stem cells cannot engraft or induce tolerance alone, so my research aims to look at other cells within the bone marrow that allow the stem cells to stick or "engraft" within the fetus. We will do this by performing bone marrow transplants into fetal mice and studying how the transplanted cells behave in the recipient. After identifying the important cells in this process we will then attempt to treat a mouse model of thalassaemia with a fetal transplant. If successful, the mice will express two different types of red blood cell (Thalassaemia cells and cells from the transplant). We will be able to study these by examining both mice blood and bone marrow. Importantly, having healthy blood cells present from the donor will means these mice do not get symptoms of thalassaemia - including anaemia and heart muscle damage.Implications of this workIf we are able to identify a specific cell that induces tolerance for fetal transplantation, we will be much closer to delivering a treatment into humans for thalassemia and other devastating diseases which can be diagnosed prenatally. Indeed, while patients with the former will survive to adulthood, there are many other conditions (such as rare metabolic conditions) where the disease may be progressing during development. Fetal stem cell transplant would offer a cure for these conditions and therefore also a better outcome by the time the baby is born.

背景200婴儿每年都在英国出生，遗传性血红蛋白疾病等血液疾病。这些疾病会影响红细胞中携带部分的氧气。地中海贫血是最常见的一种。治疗涉及患者整个生命中的定期输血。这可能会导致以后生命中的多个问题，包括糖尿病，心脏病和骨骼变薄，因为铁中铁的过多积累。此外，许多人需要复杂的多学科护理，并且由于住院和症状问题而导致的学校和工作中断。目前，可以用骨髓移植治愈丘脑。这涉及给供体干细胞，但是这不经常提供，因为涉及很大的风险。患者的免疫系统和移植中的免疫细胞都可能引起重大问题，包括死亡。也存在着相当大的移植与宿主疾病的风险，其中移植的细胞开始攻击受体。因此，对免疫系统在这种情况下的运作方式进行了大量研究。胎儿干细胞移植胎儿的免疫系统是独一无二的，因为它仍在学习称为朋友（“宽容”）或敌人所需的东西。研究已经表明，目前进行移植可以使移植能够耐受性，而无需给予任何药物抑制免疫系统，从而避免了产后骨髓移植的许多风险。但是，我们无法使用它来治疗诸如Thalassaemia之类的血红蛋白病的模型。我们的研究我们知道，干细胞不能单独植入或诱导耐受性，因此我的研究旨在查看骨髓中的其他细胞，以使干细胞在胎儿内粘贴或“植入”。我们将通过将骨髓移植到胎儿小鼠中并研究受体中的移植细胞的行为方式来做到这一点。在此过程中识别重要的细胞后，我们将尝试用胎儿移植治疗丘脑的小鼠模型。如果成功，小鼠将表达两种不同类型的红细胞（Thalassexyplant和移植中的细胞）。我们将能够通过检查小鼠血液和骨髓来研究它们。重要的是，从供体中出现健康的血细胞将意味着这些小鼠不会获得丘脑症的症状 - 包括贫血和心肌损害。这项锻炼的刺激性，如果我们能够识别一个特定的细胞，该细胞能够诱发胎儿移植的胎儿，我们将对thalassia和其他愿意诊断的人类造成对人类的治疗。确实，尽管有前者的患者将幸存到成年，但在发育过程中疾病可能正在发展，还有许多其他疾病（例如罕见的代谢条件）。胎儿干细胞移植将为这些疾病提供治疗方法，因此在婴儿出生时也会有更好的结果。

项目成果

COVID-19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS-CoV-2 infection.

• DOI: 10.1111/1471-0528.16974
• 发表时间: 2022-01
• 期刊: BJOG : an international journal of obstetrics and gynaecology
• 作者: Beesley MA;Davidson JR;Panariello F;Shibuya S;Scaglioni D;Jones BC;Maksym K;Ogunbiyi O;Sebire NJ;Cacchiarelli D;David AL;De Coppi P;Gerli M
• 通讯作者: Gerli M

Fetal body MRI and its application to fetal and neonatal treatment: an illustrative review.

• DOI: 10.1016/s2352-4642(20)30313-8
• 发表时间: 2021-06
• 期刊: The Lancet. Child & adolescent health
• 作者: Davidson JR;Uus A;Matthew J;Egloff AM;Deprez M;Yardley I;De Coppi P;David A;Carmichael J;Rutherford MA
• 通讯作者: Rutherford MA

Complete Resection of Necrotic Bowel Improves Survival in NEC Without Compromising Enteral Autonomy.

坏死肠的完全切除可提高 NEC 的生存率而不影响肠自主权。

• DOI: 10.1016/j.jpedsurg.2023.10.012
• 发表时间: 2024
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Pardy C

Thoracoscopic Stage Internal Traction Repair Reduces Time to Achieve Esophageal Continuity in Long Gap Esophageal Atresia.

胸腔镜阶段内牵引修复可缩短长间隙食管闭锁实现食管连续性的时间。

• DOI: 10.1055/a-2235-8766
• 发表时间: 2024
• 期刊: official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie
• 作者: Borselle D

Fetal magnetic resonance imaging (MRI) enhances the diagnosis of congenital body anomalies.

胎儿磁共振成像 (MRI) 增强了先天性身体异常的诊断。

• DOI: 10.1016/j.jpedsurg.2021.10.033
• 发表时间: 2022
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Davidson JR