Macrophage Therapy for Acute Liver Failure

需要：急性肝功能衰竭(ALF)除了肝移植外没有其他有效的治疗方法，由于其相关的发病率/死亡率、医疗保健提供者的费用以及供体肝脏的稀缺，其使用受到限制。扑热息痛(对乙酰氨基酚)过量是西方世界最常见的原因。扑热息痛过量的唯一治疗方法是乙酰半胱氨酸，只有在过量治疗后不久(大约8小时内)开始治疗时，才能预防ALF。对于ALF的其他原因，目前还没有特效的治疗方法。解决方案：该建议的产品是一种现成的、同种异体的、交替激活的巨噬细胞疗法，来自“通用的”O型供者单核细胞，不需要进一步的供受者配型。该产品将被冷冻，储存在治疗点附近，并在输液前按需解冻。理由：交替激活的巨噬细胞减少ALF小鼠模型的肝坏死和炎性细胞因子，并增加增殖的肝祖细胞。我们的解决方案以这些世界领先的临床前研究为基础，成功地为慢性肝病患者提供了巨噬细胞治疗(Match试验，由DPFS，Moroni等人支持。最近完成了扑热息痛毒性的第一阶段试验(《柳叶刀》EBioMedicine 2019年https://www.ebiomedicine.com/article/S2352).Development计划：我们将在前18个月完成IMPD并获得临床试验授权)。这一过程将由细胞和基因治疗弹射器指导，并建立在我们之前在CTA应用于肝脏疾病巨噬细胞治疗方面的成功的基础上。在接下来的30个月中，将在扑热息痛引起的急性肝损伤患者的第一阶段临床试验中提供同种异体或交替激活的巨噬细胞的第一阶段临床试验。这项研究建立在巨噬细胞疗法治疗慢性肝病的临床试验和急性扑热息痛过量的第一阶段临床试验方面的独特本地专业知识。如果这项研究成功，将为巨噬细胞疗法治疗这种疾病的随机对照试验铺平道路，重要的是将促进巨噬细胞疗法针对其他原因的急性肝功能衰竭的发展。

Need: Acute liver failure (ALF) has no effective treatment other than liver transplantation, which has limited use because of its associated morbidity/mortality, expense to the health provider and the scarcity of donor livers. Paracetamol(acetaminophen) overdose is the commonest cause in the Western world. The only treatment for paracetamol overdose is acetylcysteine, which is preventative with regard to ALF only if treatment starts soon after overdose (within around 8h). For other causes of ALF there is currently no specific treatments. Solution: The proposed product is an off-the-shelf, allogeneic, alternatively-activated, macrophage cell therapy derived from 'universal' blood group O donor monocytes requiring no further matching of donor to recipient. The product will be frozen, stored close to the point of treatment and thawed on demand prior to infusion.Rationale: Alternatively-activated macrophages reduce liver necrosis and inflammatory cytokines, and increase proliferating hepatic progenitors in mouse models of ALF. Our solution is anchored by these world-leading pre-clinical studies, success in delivering macrophage therapy to patients with chronic liver disease (MATCH Trial, supported by DPFS, Moroni et al. Nature Medicine 2019) and the recent completion of the first phase 1 trial in paracetamol toxicity (Lancet EBioMedicine 2019 https://www.ebiomedicine.com/article/S2352).Development plan: In the first 18 months we will complete the IMPD and obtain a clinical trial authorisation. This process will be guided by the Cell and Gene Therapy Catapult and builds on our previous success with CTA applications for macrophage cell therapy in liver disease. In the following 30 months will deliver a phase 1 clinical trial of allogeneic, alternatively activated, macrophages in a phase 1 clinical trial in patients with paracetamol-induced acute liver injury. This builds on the unique local expertise in clinical trials of macrophage cell therapy in chronic liver disease and phase 1 clinical trials in acute paracetamol overdose.If successful this study paves the way for a randomised controlled trial of macrophage cell therapy for this condition and importantly will facilitate the development of macrophage cell therapy for other causes of acute liver failure.