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.

背景英国每年有超过 200 名婴儿出生患有血红蛋白病等遗传性血液疾病。这些疾病影响红细胞的携氧部分。地中海贫血是最常见的一种。治疗包括患者一生定期输血。这可能会导致晚年出现多种问题，包括糖尿病、心脏病以及由于组织中铁过多积聚而导致骨质疏松。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对学校和工作造成相当大的干扰。目前，地中海贫血可以通过骨髓移植治愈。这涉及提供捐赠干细胞，但这种情况并不经常提供，因为存在重大风险。患者的免疫系统和移植物中的免疫细胞都可能导致严重的问题，包括死亡。还存在相当大的移植物抗宿主病风险，其中移植的细胞开始攻击受体。因此，人们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特的，因为它仍在学习需要什么来称呼朋友（“宽容”的“自我识别”）或敌人。研究已经表明，此时进行移植可以使移植产生耐受性，而不需要给予任何药物来抑制免疫系统，从而避免了许多产后骨髓移植的风险。然而，我们还无法使用它来治疗地中海贫血等血红蛋白病模型。我们的研究我们知道干细胞不能单独植入或诱导耐受性，因此我的研究旨在观察骨髓内允许干细胞生长的其他细胞粘住或“植入”胎儿体内。我们将通过对胎儿小鼠进行骨髓移植并研究移植细胞在受体体内的行为来实现这一目标。在确定了这一过程中的重要细胞后，我们将尝试通过胎儿移植来治疗地中海贫血小鼠模型。如果成功，小鼠将表达两种不同类型的红细胞（地中海贫血细胞和移植细胞）。我们将能够通过检查小鼠血液和骨髓来研究这些。重要的是，拥有来自捐赠者的健康血细胞将意味着这些小鼠不会出现地中海贫血的症状，包括贫血和心肌损伤。这项工作的意义如果我们能够识别出诱导胎儿移植耐受的特定细胞，我们将更接近于为人类提供地中海贫血和其他可在产前诊断的破坏性疾病的治疗方法。事实上，虽然患有前者的患者可以存活到成年，但在许多其他疾病（例如罕见的代谢疾病）中，疾病可能在发育过程中进展。胎儿干细胞移植可以治愈这些疾病，因此在婴儿出生时也能获得更好的结果。

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

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

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

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