Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Development of adrenal organoids after intracutaneous adrenal cell auto-transplantation for primary adrenal insufficiency in a porcine implanted biodegradable temporising matrix (#89)

Brigette M Clarke 1 2 3 , Svjetlana Kireta 1 3 , Julie Johnston 1 3 , James Kollias 4 , John Greenwood 5 , Chris Christou 6 , Patrick Coates 1 3 7 , David Torpy 1 2
  1. University of Adelaide , Adelaide, South Australia, Australia
  2. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  3. Centre for Clinical and Experimental Transplantation, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  4. 287 Angas Street, Adelaide, South Australia, Australia
  5. Royal Adelaide Hospital, Adelaide, SA, Australia
  6. Preclinical Imaging and Research Laboratories, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  7. Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia

Recognising the limitations of current therapies for primary adrenal insufficiency (PAI), novel treatments that better replicate dynamic physiologic corticosteroid secretion under ACTH control are required (1). The aim of this experiment was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a porcine model, adapting methods successfully used for intra-cutaneous pancreatic islet cell transplantation using a biodegradable temporising matrix (BTM) (2).

BTM material was engrafted and auto-ACT undertaken by bilateral adrenalectomy followed by isolation, culture and intracutaneous injection of adrenocortical cells (ACs) into the pre-prepared skin site (Figure). Pharmacologic corticosteroids were administered and blood sampling undertaken at serial time points. Clinical signs were monitored for adrenal insufficiency and corticosteroids weaned as tolerated. The graft was excised at end-point for analysis. Outcome measures included detection of ACs at the transplant site, systemic hormone levels and hydrocortisone independence.

Transplanted AC survival and proliferation was demonstrated macroscopically, histologically and by gene expression (Figure) in 1 of 3 transplant recipients. Post-transplantation, all subjects survived to the pre-determined end point, though corticosteroids were unable to be completely ceased. Interpretation of systemic hormone levels was confounded by identification of accessory adrenals and regenerative cortical tissue within the adrenal bed post-mortem.  Symptoms of adrenal insufficiency varied dependent on the degree of remnant/regenerative adrenal tissue.   

 

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ACT in a large animal model has not previously been attempted, yet it is an important step towards clinical translation. These results demonstrate potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient functioning, number or regeneration of transplanted cells. Further studies are required to optimise cell isolation and culture methods, develop means to objectively evaluate isolate quality prior to transplantation and determine cell yields required for clinically significant function.

  1. (1) Graves LE, Torpy DJ, Coates PT, Alexander IE, Bornstein SR, Clarke B. Future Directions for Adrenal Insufficiency: Cellular Transplantation and Genetic Therapies. Journal of Clinical Endocrinology & Metabolism. 2023.
  2. (2) Rojas-Canales D, Walters SN, Penko D, Cultrone D, Bailey J, Chtanova T, et al. Intracutaneous Transplantation of Islets within a Biodegradable Temporizing Matrix (BTM) as an Alternative Site for Islet Transplantation. Diabetes. 2023.