Exosome-based Gene Therapy for Huntington's Disease

亨廷顿氏病（HD）是一种毁灭性的神经退行性疾病，相对罕见（与帕金森氏症和阿尔茨海默氏症相比），但在英国，每10000人中就有1人患有这种疾病。亨廷顿舞蹈症是一种慢性、缓慢进展的遗传性疾病，由单个基因（亨廷顿蛋白基因）突变引起，通常在症状出现20年后，患者会出现精神错乱和卧床不起。这种疾病给患者及其家属带来了巨大的负担。目前还没有治愈HD的方法，很大程度上是由于治疗性化合物无法通过血脑屏障，以足够的水平进入大脑的受影响部位，从而产生临床疗效。通过药物治疗的组合，症状和体征得到了相对较好的控制，但这些治疗都无法阻止疾病的破坏性进展。虽然治疗性化合物正在积极开发以治疗HD，但将这些化合物输送到大脑是它们成功发展为可广泛使用的治疗方法的主要障碍。在这个应用程序中，我们计划为这个主要问题开发一个全新的解决方案。在36个月的时间里，我们将开发一种新的治疗方法，可以关闭突变的亨廷顿蛋白基因，并且可以成功地通过血脑屏障进入大脑，使用被称为外泌体的天然小颗粒。外泌体是非常小的，脂肪包裹的颗粒，是由身体的所有细胞自然产生的，我们已经利用它来将药物输送到大脑中，通过对它们进行修饰，使它们在表面显示出小分子，使它们在注射到身体的静脉后能够进入大脑。这将为测试许多已被证明可以降低突变亨廷顿基因水平的化合物打开大门。如果我们能够成功地在HD上做到这一点，这将为外泌体方法应用于治疗许多其他目前无法治愈的神经退行性疾病打开大门。在这项工作的过程中，我们的目标是实现以下目标：生产一种含有关闭亨廷顿蛋白基因的药物的优化外泌体颗粒，并在培养细胞中进行初步测试。然后测试这种优化的外泌体药物是否能到达受HD影响的大脑部位，并了解需要多大剂量的外泌体药物才能达到大脑中所需的药物活性水平。这项工作将在健康小鼠身上进行。在所有必要的方法和信息到位之后，我们将在携带亨廷顿基因突变的老鼠身上测试外泌体药物，我们将评估这种新疗法在老鼠体内预防或逆转疾病发展过程的能力。

Huntington's disease (HD) is a devastating neurodegenerative disease that is comparatively rare (compared with Parkinson's and Alzheimer's diseases) but which nevertheless affects 1 in 10,000 people in the UK. HD is a chronic, slowly progressive inherited disorder caused by mutations in a single gene (the huntingtin gene) that leave patients demented and bedridden typically 20 years after the onset of symptoms. This disease represents an immense burden on patients and their families. Currently there is no cure for HD available due largely in part to the inability of therapeutic compounds to cross the blood brain barrier and enter affected parts of the brain at sufficient levels for clinical benefit. Symptoms and signs are managed relatively well by a combination of medical treatments, but none of these treatments halts the devastating progression of the disease.While therapeutic compounds are being actively developed to treat HD, the delivery of these into the brain is the major impediment to their successful development into treatments that could be widely used. In this application we plan to develop an entirely new SOLUTION to this major problem. Over the course of 36 months we will develop a new treatment that can switch off the mutant huntingtin gene AND that can successfully cross the blood brain barrier to enter the brain using small, natural particles called exosomes. Exosomes are very small, fat encapsulated particles that are generated naturally by all cells of the body and that we have exploited for the delivery of drugs into the brain by modifying them in such a way that they display small molecules on their surface that allow them to home into the brain following their injection into a vein in the body. This will open the door to testing many compounds that have been proven to reduce the levels of the mutant Huntingtin gene. If we are able to do this successfully for HD this will open the door to the application of the exosome methods to treat many other currently incurable neurodegenerative diseases.During the course of this work we aim to achieve the following:1. To produce an optimised exosome particle containing the drug to switch off the Huntingtin gene and to test this initially in cells in culture.2. To then test whether this optimised exosome drug can reach the parts of the brain affected by HD, and to understand what doses of exosome drug are required in order to achieve the required levels of drug activity in the brain. This work will be carried out in healthy mice.3. Having put all of the necessary methods and information in place we will then test the exosome drug in mice which carry the Huntingtin gene mutation and we will evaluate this new therapy for its ability to prevent or reverse the development of the disease process in the mice.