Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive childhood disease characterised by isolated glucocorticoid (GC) deficiency. 25% of cases are due to mutations in melanocortin-2-receptor (MC2R) and a further 20% due to mutations in melanocortin 2 receptor accessory protein (MRAP). The condition is fatal unless treated early. Treatment is in the form of life-long glucocorticoid replacement with frequent monitoring throughout life. The normal adrenal gland produces cortisol in a diurnal and ultradian manner. This pattern of cortisol production matters and dysregulation is associated with adrenal diseases as well as depression and obesity. No drug or drug delivery system has yet been able to reproduce normal cortisol secretion. Hence, PAI patients on steroid replacement have an increased mortality and morbidity from too much or too little medication. Current treatment is inadequate resulting in increased morbidity and mortality from over and under replacement. There is growing awareness/need for better treatments in PAI. The ability to regrow/regenerate an adrenal gland, allowing physiological cortisol responses during stress and illness, could provide a cure in PAI and transform lives. Gene therapy offers a promising alternative to cure genetic diseases and transform care. We recently generated a novel FGD mouse model that lacks MRAP expression, which perfectly recapitulates human FGD. Previous published work on another mouse model of adrenal insufficiency have shown promise of using adeno-associated viruses (AAVs) to deliver missing factors and to restore adrenal steroid production. Unfortunately, the effects were short lived. Our study aims to target the stem cell niche of the adrenal gland in MRAP-knockout animals to restore expression of MRAP. By targeting the stem cell niche we hope to be able repopulate the adrenal gland through-out a lifetime. This would provide proof of concept data for future studies on humans with FGD as well as other forms of adrenal insufficiency.
Funding Notes:
The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for a research studentship, for a clinically qualified candidate to commence in October 2022, leading to a PhD degree from The QMUL Faculty of Medicine and Dentistry.
This studentship will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. The Studentship will cover the successful candidate’s current clinical salary and will include PhD fees (at home fee rate) with up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.
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Application Web Page:
https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-W6ZF-09&code2=0013
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