The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub

用人多能干细胞（hPSC）衍生产物修复受伤或患病的人体的能力正在成为现实的治疗选择。然而，这带来了一些重大挑战：1）这可以安全地完成吗？2)这样做是否有益且具有竞争力？也就是说，它的治疗效果和现有的一样好或更好; 3）我们能在治疗所有可能需要这种治疗的患者所需的规模上做到这一点吗？ 在这个新的中心，我们将围绕两种特定的治疗药物研究这些问题。第一种方法是制造多巴胺神经细胞，以取代帕金森病（PD）患者大脑中丢失的细胞。第二个涉及制造血液中对凝血至关重要的特定成分-即从hPSC衍生的巨核细胞产生的血小板。这两种细胞产品和与其使用相关的疾病不被视为该补助金的主要产出，而是将有助于我们的工作背景化，其主要目的是建立一个平台，通过该平台可以将任何hPSC衍生的治疗带到临床。我们有三个主要目标：第一个涉及在实验室中生长的细胞中观察到的获得性遗传变化，以及这对我们的hPSC/细胞产品的安全性意味着什么。每个细胞都有DNA，其中包含我们所有的基因，细胞之间，将有自然的变化沿着随机的错误和失误。这些变化中有许多是无关紧要的，而另一些则可能是有害的。我们需要回答的问题是，我们能否可靠地检测出hPSC和我们从中产生的细胞中的不良遗传变异，同时也能识别出那些不重要且可以安全忽略的遗传变化。这显然不是一个容易回答的问题，但我们要做的是观察许多不同hPSC/产品中基因的变化，然后将我们发现的结果与包含此类基因变化的联系信息的数据库进行比较。与已知的人类疾病和癌症。这将使我们能够制定指南，然后有望被相关监管机构采用，并应用于任何进入临床的hPSC衍生疗法。 我们的第二个目标是解决与我们如何以大量患者临床使用所需的数量和质量生产hPSC衍生产品相关的主要问题。目前，我们在实验室开发的许多方案都运行良好，但我们使用的试剂不是患者所需的等级-所谓的GMP等级。因此，我们将寻求开发必要的临床兼容方案，然后研究如何扩大和扩大我们感兴趣的细胞的生产，以便最终所有相关患者都能从这些类型的治疗中受益。对于某些疾病，这将是非常直接的，因为我们只需要相对较少的细胞来治疗患者-例如，单个PD患者需要50万到100万个细胞。在其他条件下，我们将需要数百万和数十亿的细胞，如血小板，这给制造业带来了巨大的挑战。因此，我们将研究如何做到这一点，这样我们就可以在临床使用所需的水平上可靠地、可重复地做到这一点。 我们最终的主要目标是开发新技术，使我们的细胞疗法在移植时更好地发挥作用。这将涉及两种主要方法;（i）使我们能够更有效地制造我们想要的细胞的技术，即，因此我们可以从我们的hPSC中制造大量细胞，以治疗患者;（ii）沉默细胞中触发免疫排斥的关键分子/蛋白质，即，当细胞移植到患者体内时，他们的免疫系统将对它们反应不那么强烈。这反过来意味着我们可以使用不那么积极的免疫抑制方案来阻止移植物被排斥，从而减少这些药物的任何副作用。

The ability to repair the injured or diseased human body with human pluripotent stem cell (hPSC) derived products is emerging as a realistic therapeutic option. However this brings with it a number of major challenges; 1) Can this be done safely? 2) Can this be done usefully and competitively? i.e. it the treatment as good or better than what is available; and 3) Can we do this at the scale needed to treat all patients that might require this type of therapy? In this new hub we will work on these issues around two particular therapeutic agents. The first involves making dopamine nerve cells to replace those lost in the brain of patients with Parkinson's disease (PD). The second involves making a specific component of blood that is vital for clotting- namely platelets generated from hPSC-derived megakaryocytes. These two cell products and the diseases linked to their use are not seen as the primary output of this grant, but rather will serve to contextualise our work, which is primarily designed to build a platform by which any hPSC-derived therapy can be brought to the clinic. We have three major aims: The first relates to acquired genetic changes seen in cells grown in the laboratory and what this means for the safety of our hPSCs/cell products. Every cell has DNA, which contains all our genes, and between cells, there will be natural variations along with random errors and mistakes. Many of these changes are of no consequence, while others may be potentially harmful. The question we need to answer is can we reliably detect the bad genetic variants in the hPSCs and the cells we produce from them, while also recognising those genetic changes that are unimportant and can be safely ignored. This is obviously not an easy question to answer, but what we will do, is look at the changes in the genes in a number of different hPSCs/products and then compare what we find with databases that contain information on the links such genetic changes have to known human diseases and cancers. This will allow us to develop guidelines, which will then hopefully be adopted by the relevant regulatory agencies and applied to any hPSC-derived therapy going to clinic. Our second aim is to address the major issues related to how we can manufacture our hPSC-derived products in the numbers and quality required for clinical use in large numbers of patients. Currently, many of the protocols we have developed in the lab, work well, but the reagents we use are not of the grade needed for use in patients- so called GMP grade. Thus we will seek to develop the necessary clinically compatible protocols and then work out how we can scale up and scale out the manufacturing of the cells we are interested in developing so that ultimately all relevant patients could benefit from these types of treatment. For some diseases, this will be quite straight forward, as we only need relatively few cells to treat patients- e.g. 500,000 to a million cells for a single patient with PD. In other conditions, we will need millions and billions of cells, such as platelets, and this creates huge challenges for manufacturing. We will therefore work on ways to do this, such that we can reliably and reproducibly do this at the level needed for clinical use. Our final major aim is to develop new techniques to make our cell therapies work better when transplanted. This will involve two main approaches; (i) Techniques to allow us to make the cells we want more efficiently, i.e. so we can manufacture large numbers of cells from our hPSCs as will be needed to treat patients and; (ii) Silencing critical molecules/proteins in the cells that trigger immune rejection, i.e. so that when the cells are grafted into patients their immune system will react to them less vigorously. This in turn will mean that we can use less aggressive immunosuppressive regimes to stop the grafts being rejected and by so doing reduce any side effects from these drugs.