Dr Hedi Claahsen, Dr Antonius Herwaarden, “The risk for developing clinical signs of cortisol deficiency in CAH and acquired adrenal insufficiency – what makes the difference?”, 75 000 €

Primary adrenal insufficiency (PAI) is a serious condition as patients miss the stress hormone cortisol. In childhood this is mostly caused by congenital adrenal insufficiency (CAH). ln adulthood the most common cause is autoimmune disease (Addison’s Disease, AD). In general, these patients are at risk to develop a life-threatening Addisonian crisis. Therefore, treatment with cortisol including stress dosing during illness is an important goal. There is an increasing number of reports of CAH patients who decide to stop cortisol treatment surprisingly without serious complaints. This is not reported in patients with AD. The mechanism of how some untreated CAH patients can survive with obviously a lack of cortisol is unknown. In our project we want to study the special situation of untreated CAH patients in more detail and want to compare these patients with patients with AD. We want to know if these patients develop complaints of Addisonian crisis or other complications. Furthermore, we want to find out which factors play a role in the protective mechanisms of CAH that differ from patients with AD. We hypothesize that other adrenal products which are markers of CAH may protect some CAH patients from signs of cortisol deficiency but we do not know if these markers are also sufficient to prevent Addisonian crisis. Furthermore, differences in the free fraction of cortisol, the active part of cortisol, may protect patients form clinical relevant complaints.

Dr Alaa El Ghoneimi,  “New standardized method for objective short and long term functional and morphological evaluation of operated CAH genitalia in children and adolescent: The EvaSurg study”, 50 000 €

Early feminizing genitoplasty for CAH female with virilized genitalia is still debated, in particular when clitoroplasty is performed, because of concerns about secondary vaginal introitus stenosis and clitoral neurovascular bundles injury. Nevertheless, this surgery lacks objective evaluation before first sexual intercourse in the literature. This study aims at evaluating clitoral sensitivity after genitoplasty with or without clitoroplasty, before first sexual intercourse, in 2 paediatric expert centers in Paris. Neurological testing of the clitoris will rely on both a specific reflex loop called clitorocavernosus reflex, quantified by electromyogram, and a sensitivity testing with clinical response to touch and vibration. Patients with clitoroplasty will be compared to non-operated CAH (genitoplasty without clitoroplasty or no genitoplasty at all). This study will provide a simple, objective and reproducible method to evaluate the results of genital surgery for virilized CAH patients. Patients and their families will be aware of the consequences of the surgery and in case of unfavorable results the surgical techniques should be reconsidered.

Dr Gerard Ruiz Babot, “Generation of human steroid-producing organoids: a new approach towards a treatment for CAH (Renewal)”, 100 000 € (AFM IFCAH)

Adrenal glands control essential bodily functions through production of hormones. People unable to make hormones suffers from adrenal insufficiency, a life-threatening condition. Stem cells can generate all cell types in the body, including adrenal cells. This project aims to produce cells in the laboratory that can produce hormones to treat patients with adrenal insufficiency. However, once introduced into humans, cells generated in the laboratory can be recognized and destroyed by the patient immune system. To avoid that, cells will be protected using small medical devices that should allow them to survive, produce hormones and control patient´s bodily functions.

Dr Andreas Schedl, “Differentiation of stem cells into adrenal organoids”, 50 000 € (AFM)

Congenital adrenal hyperplasia is a devastating disease that is caused by defects in one of the genes required for hormone production. Correcting the defective gene within adrenal stem cells represents a potential cure that would ensure continuous supply of functioning steroidogenic cells throughout life. We are developing strategies to differentiate stem cells into adrenal cells with the long-term goal to transplant them into patients. During the past funding period we have identified conditions that direct cells into early adrenal cells, but the efficiency is still relatively low. Here we will further fine-tune conditions and test out transplantation in a model system to provide a proof of principle that this approach may in the future be suitable for clinical applications.

Pr Gary Hammer, “Transcriptional programs involved in ACTH-induced hyperplasia – Implication of the transcription factor Hhex in adrenal differentiation and response to chronic hormonal challenges.”, 125 000 €

The adrenal pathology in CAH results from a combination of unrestrained cellular proliferation and dysfunctional steroid production. However, the rules that govern the normal coupling of these processes are not understood. New technology has enabled us to uncover novel cell populations within the adrenal. We have determined unique gene signatures of these populations at a single-cell level. We are now in the process of defining the rules underlying proliferation and differentiation programs in normal homeostasis and disease. We have identified HHEX as a new down-regulated target of ACTH restricted to zona fasciculata. We propose that its prolonged ACTH-dependent modulation contributes to aberrant differentiation in CAH. Using single-cell methods, we will examine transcriptional changes in the adrenal after ACTH exposure. In parallel, the analysis of a mouse model of Hhex deficiency will determine the contribution of HHEX to ACTH-regulated programs in health and disease. This combined approach will improve our knowledge of CAH and adrenal deficiency.