Generation of functional adrenocortical organoids from mice and humans and their preclinical testing as cell-based therapy for adrenal insufficiency

从小鼠和人类中生成功能性肾上腺皮质类器官及其作为肾上腺功能不全细胞疗法的临床前测试

• 批准号: MR/X021017/1
• 负责人: Leonardo Guasti
• 金额: $ 63.95万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021017%2F1
• 关键词: Generation; functional; adrenocortical; organoids; mice; Generation; functional; adrenocortical; organoids; mice

The adrenal glands are part of the endocrine system, and their function is to release hormones into the blood system. Each adrenal gland is composed of two distinct parts, an outer cortex and an inner medulla. The adrenal cortex is essential for life as it produces steroid hormones: glucocorticoids (such as cortisol) regulate body metabolism and help us fight infections, and mineralocorticoids (such as aldosterone) mainly affect blood pressure. Adrenal cortex disorders can cause our adrenal glands to produce too much or not enough hormones; adrenal insufficiency occurs when glucocorticoids, and sometimes mineralocorticoids, cannot be generated in sufficient amounts. Adrenal insufficiency can be caused by mutations in genes essential for adrenal function, autoimmune disease, or tuberculosis infection of the glands; more recently, it has also been reported that SARS-CoV-2 (the causative agent for Coronavirus disease COVID-19) can infect the adrenal glands and cause adrenal insufficiency in some patients. Adrenal insufficiency is treated with medication to replace the missing hormones, and patients must take these medications for the rest of their life. These treatments are far from perfect, and the overall management of patients can be very challenging for specialists and patients alike; for example, patients may have sudden severe symptoms, especially when stressed as a result of an illness, fever, surgery, or dehydration and therefore must always carry a medical alert card or tag in order to ensure rapid treatment to prevent shock, seizure, or coma. Scientists are striving to develop novel curative treatments for patients with adrenal insufficiency, and important pre-clinical steps have been achieved in the field of gene- and cell-based therapies. Our laboratory has a long-lasting interest in the biology of the adrenal gland and recently, with a ground-breaking study, we have been able to generate functional adrenal cells starting from cells extracted from urine of patients with inborn adrenal disorders. The overall goal of this project is to establish, for the first time, adrenal organoids: these are mini organs generated in a dish, that retain the physiological function of the tissue they are generated from, and hence, can be considered 'avatars' of the tissue of origin, the adrenal cortex in this case. This project would allow us to fully characterise adrenal organoids in mice and humans, in both sexes and established from young and older donors. Crucially, when function is retained long-term, organoids could potentially be used to replace the patients' non-functioning gland; to test this, we will use an appropriate pre-clinical model, namely mice where a gene has been removed and recapitulating quite accurately the rare genetic disorder Congenital Adrenal Hyperplasia. This model has been generated and characterised by our collaborators at the University of Edinburgh, UK. Here, organoids will be transplanted in the external part of the kidneys, and we will assess whether the cardinal features of the Congenital Adrenal Hyperplasia (deficiency in glucocorticoids and mineralocorticoids) can be reversed. We believe this project will accelerate the translation of promising bench research to the patient over the next 5-10 years.

肾上腺是内分泌系统的一部分，它们的功能是将激素释放到血液系统中。每个肾上腺由两个不同的部分组成，一个外层皮质和一个内部髓质。肾上腺皮质对生命至关重要，因为它会产生类固醇激素：糖皮质激素（例如皮质醇）调节人体代谢，并帮助我们抗击感染，而盐皮质激素（例如醛固酮）主要影响血压。肾上腺皮质疾病会导致我们的肾上腺产生过多或没有足够的激素。当糖皮质激素（有时甚至是矿物皮质激素）无法以足够量产生时，肾上腺功能不全。肾上腺功能不全可能是由肾上腺功能，自身免疫性疾病或腺体结核病感染所必需的基因突变引起的。最近，还报道说，SARS-COV-2（冠状病毒疾病的病毒剂COVID-19）可以感染肾上腺并引起某些患者的肾上腺不足。用药物治疗肾上腺功能不全，以替代丢失的激素，并且患者一生都必须服用这些药物。这些治疗远非完美，患者的整体管理对于专家和患者来说可能非常具有挑战性。例如，患者可能会出现突然的严重症状，尤其是由于疾病，发烧，手术或脱水而受到压力，因此必须始终携带医疗警报卡或标签，以确保快速治疗以防止休克，癫痫发作或昏迷。科学家正在努力为肾上腺功能不全的患者开发新的治疗疗法，并且在基于基因和细胞的疗法领域已经实现了重要的临床前步骤。我们的实验室对肾上腺的生物学具有持久的兴趣，最近，通过一项开创性的研究，我们能够从从先天肾上腺疾病患者的尿液中提取的细胞开始产生功能性肾上腺细胞。该项目的总体目的是首次建立肾上腺器官：这些是在盘子中产生的迷你器官，保留了它们由它们产生的组织的生理功能，因此可以认为是原始组织的“ avatars”，在这种情况下，肾上腺皮质。该项目将使我们能够完全表征小鼠和人类，性别和年轻捐助者建立的肾上腺器官。至关重要的是，当功能长期保留时，可能会使用器官来替代患者的无功能腺体。为了测试这一点，我们将使用适当的临床前模型，即已去除基因并准确地概括稀有遗传疾病先天性肾上腺增生的小鼠。该模型是由我们在英国爱丁堡大学的合作者生成和特征的。在这里，类器官将在肾脏的外部移植，我们将评估先天性肾上腺增生的基本特征（糖皮质激素和矿物皮质激素的缺乏）是否可以逆转。我们认为，该项目将在未来5 - 10年内加速对患者的有前途的基准研究的翻译。