Determination of optimal medication to support efficacy of hESC-derived transplants for Parkinson's disease and assessment of side effect risk.

帕金森氏症（PD）影响着英国超过12万名患者，全球超过630万人。帕金森病患者可能会服用3到4种不同的药物来缓解症状，此外，他们中的许多人患有抑郁症，因此服用抗抑郁药，但目前尚无治愈方法。这种疾病是由大脑中含有化学物质多巴胺的细胞丢失引起的，已经证明可以从胚胎的大脑中取出这些细胞（一旦它们开始产生多巴胺）并将其植入PD患者的大脑中。到目前为止，一些接受了这些移植的患者在几个月或几年后，他们的症状有了很大的改善，他们的药物用量也有所减少。然而，使用胚胎在伦理和方法上都是不可持续的，因此需要其他方法来制造这些细胞。我们现在有技术将人类胚胎干细胞改造成适合移植的脑细胞。有了这项技术，我们可以制造足够的细胞，以安全可靠的方式移植许多患者，并计划在2019年进行新的临床试验。然而，在将干细胞移植到患者身上之前，还存在一些突出的问题。先前的临床试验表明，移植胎儿细胞的效果是不一致的。虽然一些患者的症状有了很大的改善，但另一些患者没有，此外，患者还经历了被称为移植物性运动障碍（GID）的运动副作用。这些运动类似于药物产生的副作用，但却是永久性的。这些副作用和可变结果的原因可能是患者在移植时服用的治疗帕金森病的药物。为了使干细胞移植成为帕金森病的一种成功的治疗选择，至关重要的是，在准备进行临床试验的新细胞中探索这些疗效和副作用问题。我们询问了500多名帕金森病患者和他们的护理人员，他们对细胞疗法最大的担忧是什么，大多数患者（超过90%）担心可能的长期副作用。重要的是，他们也愿意做出任何改变，他们可能需要他们的药物，以确保最好的结果，如果他们进行移植。这项研究将在大鼠身上进行两项实验，以观察药物对移植的影响。我们可以在老鼠大脑的一侧重建帕金森氏症，这样它们表面上是健康的动物，但我们可以探索当我们给帕金森药物时，这些细胞在修复大脑损伤方面有多好。实验1将是一个较短的实验，目的是观察帕金森病患者服用的每种药物对移植物的影响。我们将看看帕金森病患者服用的每种药物的例子，也包括患者经常服用的抗抑郁药等药物。第二个更长时间的实验将使我们能够评估用于临床试验的每组细胞的副作用风险。这些实验是基于药物治疗的患者正在参加目前的胎儿细胞试验，并将使用一些将用于临床试验的细胞。这些实验很重要，可以让我们指导临床试验，选择合适的患者纳入临床试验，并确定副作用的风险。我们也许能够确定哪些药物能最大限度地提高移植成功率，哪些药物不应该用于接受移植的患者。这些信息的产生是为了支持这项临床试验，但其结果将与全球所有计划中的帕金森病细胞移植试验相关，因此也将提供给他们。

Parkinson's disease (PD) affects over 120 000 patients in the UK and over 6.3 million people around the globe. A patient with PD could be on 3 or 4 different drugs to help with their symptoms, and additionally many of them suffer with depression so are taking antidepressants, while no cure exists. The disease is caused by the loss of cells in the brain that contain the chemical dopamine and it has been proven possible to take these cells from the brains of embryos (once they have started to make dopamine) and implant them into the brains of people with PD. Some patients who have received these transplants so far have had big improvements in their symptoms and a reduction in their medication after several months or years. However, using embryos is ethically and methodologically unsustainable, so alternative ways of making these cells is needed. We now have the technology to engineer human embryonic stem cells into the right kind of brain cells for transplantation. With this technology we can make enough cells to transplant many patients in a safe and reliable way and there are plans for a new clinical trial in 2019. However, there are some outstanding problems before we can take stem cells into patients. Previous clinical trials showed that the effects of transplanted foetal cells were inconsistent. While some patients had huge improvement to their symptoms others had none, and in addition, patients experienced motor side effects known as graft-induced dyskinesia (GID). These movements are similar to the side effects produced by the drugs, but are permanent. The cause of these side effects and variable outcomes may be the drugs patients were taking to treat their Parkinson's disease at the time of transplantation. For stem cell transplantation to become a successful treatment option for PD, it is vital that both these issues of efficacy and side effects are explored with the new cells that are ready for clinical trial. We asked over 500 people with Parkinson's disease and their carers what their biggest concerns were for cell therapy, and the majority of patients (over 90%) were worried about the possibility of long term side effects. Importantly, they were also willing to make whatever changes they might need to their medication to ensure the best possible outcome should they have a transplant.This study will carry out 2 experiments in rats to look at the effect of medication on transplants. We can recreate Parkinson's disease on one side of a rats brain such that they are outwardly healthy animals, but we can then explore how good these cells are at repairing the damage in the brain when we give the parkinson's drugs. Experiment 1 will be a shorter experiment to look at how each drug type that is taken by a person with Parkinson's disease might affect the graft. We will look at examples of each type of drug taken by a person with Parkinson's disease and also include drugs such antidepressants that patients are also often taking. A second, longer experiment will allow us to evaluate the risk of side effects from each set of cells that will be used in the clinical trial. These experiments are based on the medications patients that are taking part in a current foetal cell trial and will use some of the exact cells that will be used in clinical trials. These experiments are important to allow us to guide the clinical trial to select the right patients for inclusion into the clinical trial and determine what the risks might be for side effects. We may be able to identify drugs that will give the best chance of graft success, or that should not be taken in someone receiving a transplant. This information is being generated to support this clinical trial but the results will be relevant to all the planned trials worldwide for cell transplantation in Parkinson's disease so will be made available to them also.