Targeting adrenal stem cells by gene therapy to rescue adrenal insufficiency in Familial Glucocorticoid Deficiency type 2 (360G-Wellcome-342384_Z_25_Z)

Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disease characterised by isolated glucocorticoid deficiency. The condition is fatal unless treated, due to adrenal crisis in the neonatal period. 20% of cases are due to mutations in melanocortin 2 receptor accessory protein (MRAP), termed FGD type 2 (FGD2). Treatment is life-long glucocorticoid replacement which is associated with morbidity and mortality, due to over- or under-replacement and inability to replicate physiology. Gene therapy offers a curative promise for genetic diseases. Our research group has generated a novel FGD mouse model lacking MRAP expression, recapitulating human FGD2. Our study aims to target the adrenal progenitor cell niche in MRAP-knockout (Mrap-/-) animals using Adeno-associated viruses (AAVs) to restore MRAP expression. By targeting these, we aim to repopulate the adrenal gland throughout a lifetime. Our aims are to (1) identify the optimal AAV serotype to transduce adrenal progenitor cells and therefore build our gene therapy construct, (2) use this to determine replacement of MRAP in adrenal progenitor cells lacking MRAP, (3) administer the gene therapy to Mrap -/- mice models and assess efficacy, safety and longevity of rescue. The project will provide proof-of-concept data for translational studies in FGD and other forms of adrenal insufficiency.