Revival of autochthonous adrenocortical stem cells in autoimmune Addison's disease

The cortex of the adrenal gland manufactures two steroid hormones, cortisol and aldosterone, that are essential for life. The activity of the adrenal cortex, including cortisol and aldosterone production, is controlled by a master regulatory hormone known as ACTH (adrenocorticotrophic hormone). Too much ACTH causes the adrenal glands to expand and to make too much cortisol. In contrast, too little ACTH causes the adrenals to shrink, and results in serious illness owing to steroid deficiency. All the cells of the adrenal cortex start life by dividing from their parent stem cells which are located around the outer edge of the adrenal gland. The proliferation and growth of these parent stem cells is also strongly regulated by the same hormone, ACTH.


Untreated, autoimmune Addison?s disease is an invariably fatal condition. The adrenal cortex becomes destroyed by an immune system attack, leading to deficiency of the vital steroid hormones, cortisol and aldosterone. During the development of Addison?s disease, the body senses the steroid hormone deficiency, so blood ACTH levels become very high (typically 20-times higher than normal). This is an attempt by the body to stimulate the adrenal cells to divide and make more of the essential steroid hormones. However, once diagnosed and treated with replacement steroid tablets, the ACTH levels fall. Critically, this leads to a worsening of the function of any remaining adrenal stem cells and further reduction in functioning adrenal tissue. The idea of the current project is to give back ACTH to people with treated autoimmune Addison?s disease in order to stimulate the stem cells in their adrenal glands back into activity. The treatment with ACTH would initially be by daily injection for 10 weeks. This could ultimately lead to recovery of adrenal gland function and people with Addison?s disease may then be able to stop their steroid medications. Their condition could be cured.

Adrenocortical tissue is highly plastic owing to capsular adrenocortical stem cells (ACSC) that are highly sensitive to their cognate growth factor: adrenocorticotrophic hormone (ACTH). During autoimmune Addison‘s disease (adrenocortical failure) the steroidogenic cells of the adrenal cortex are attacked and destroyed by the immune system, with the steroidogenic enzymes as the targets of immune attack. Because the ACSC progenitors do not express the steroidogenic enzymes that are the markers of terminal differentiation of adrenocortical cells, it is probable that they are spared from destruction in autoimmune Addison‘s disease and become quiescent following exogenous suppression of their ACTH driver. This study will use a staged regimen of administered recombinant ACTH (‘synacthen‘) to re-activate dormant endogenous ACSCs and regenerate functional steroidogenesis in 12 patients with autoimmune Addison‘s disease. The first 10 week phase of the study will use once daily ACTH injections. The second phase will use a subcutaneous ACTH infusion, either infused at a constant rate over 24 hours or as a 12hr pulsatile infusion to stimulate ACSC proliferation, differentiation and steroidogenesis. Response to therapy will be judged by conventional endocrine markers of adrenal function. This pragmatic study will provide valuable proof of principle that ACSCs remain viable and ACTH responsive, even in established adrenal failure. In addition, this investigation has the potential to launch a new field of regenerative adrenal therapies, with potential benefit for up to 8,500 individuals in the UK with autoimmune adrenocortical failure, a chronic and morbid condition.