Professor Felix Beuschlein, Professor Gerald Schwank , “HAX-Edit: A Human Adrenal Ex Vivo Gene-Editing Platform for Translational CAH Gene Therapy”, 150000 euros
Congenital adrenal hyperplasia (CAH) is a genetic condition that affects how the adrenal glands produce essential hormones. Current treatments require lifelong medication, but they do not fully mimic the body’s natural hormone rhythms and can lead to long-term health problems. This project develops a new approach called HAX-Edit, which allows researchers to test gene therapies directly in living human adrenal tissue. By using advanced gene-editing tools and targeted delivery methods, the platform can assess the safety and efficacy of these therapies. The goal is to repair the faulty gene responsible for CAH and restore normal hormone production. This work fills an important gap by generating human data and helps pave the way for future clinical trials in adults with CAH.
Doctor Typhanie Dumontet, Professor Felix Beuschlein, “Targeting HHEX-mediated lipophagy in Congenital Adrenal Hyperplasia (CAH)”, 150000 euros
Congenital adrenal hyperplasia (CAH) is an adrenal gland disorder marked by low cortisol production, accumulation of steroid precursors, and androgen excess. Lifelong synthetic glucocorticoids remain the main treatment, but along with excess androgens, they often cause significant clinical complications. While adjunct therapies can reduce androgens and enable lower steroid doses, patient responses are variable. This project explores a new approach centered on the transcription factor HHEX, identified by single-cell transcriptomics in prior research supported by IFCAH. Our recent findings showed that HHEX helps adrenal cells retain lipid stores and produce steroid precursors. Thus, we will test whether inhibiting HHEX and stimulating “lipophagy” (lipid breakdown) could be a therapeutic strategy in mice and in human cell models. In parallel, we will assess whether HHEX genetic variants are linked to CAH severity and treatment response.
Professor Roland Stimson, Professor Andrew Ruth, Doctor Mark Nixon, “Corticosterone as a metabolically safer glucocorticoid to treat CAH”, 150000 euros
Glucocorticoids (stress hormones) are the primary treatment for CAH, most commonly using hydrocortisone (cortisol) to replace glucocorticoid deficiency and to reduce excessive levels of male sex hormones (androgens). However, patients have higher levels of obesity, diabetes and reduced quality of life, in part due to current treatments. Humans produce another glucocorticoid called corticosterone. We found that corticosterone can decrease androgen levels with reduced side effects. However, no drug form of corticosterone exists at present so we plan to manufacture a preparation of corticosterone that can be given to humans for a subsequent 4-week study comparing it with hydrocortisone in adults with CAH, to determine if corticosterone may be a safer treatment in the longer term.
Professor Ian Alexander, Doctor Lara Graves, “Towards human translation: a humanised pre-clinical system for development of gene therapy for CAH“, 150000 euros
Congenital adrenal hyperplasia (CAH) is a lifelong genetic condition that places a major daily burden on children and families, requiring constant medication, monitoring and illness management. Our long-term goal is to develop a one-time gene editing treatment that could correct the underlying cause of the disease, rather than simply managing its symptoms. Our team has already achieved a world-first breakthrough by successfully editing the CAH gene in the adrenal gland of animal models, with lasting improvement. The next challenge is to make this approach work safely and effectively in human tissue. In this project, we will use donated human adrenal tissue to build a unique model that allows us to test and refine gene therapy in living human adrenal cells. This is a critical step toward translating our laboratory discoveries into a future curative treatment for children and adults living with CAH.
