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

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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.