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

点击翻译按钮获取中文摘要

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.