Ian Alexander and Lara Graves, Gene Therapy Research Unit, Sydney Children’s Hospitals Network

“Genomic Editing as a Therapeutic Approach to Congenital Adrenal Hyperplasia“, 150000 Euros for 3 years

In Congenital Adrenal Hyperplasia, a faulty gene renders the adrenal gland unable to produce cortisol (stress hormone) and aldosterone (salt hormone). This can lead to catastrophic health crisis with collapse and death. High levels of male-type hormones may also lead to masculinisation of genitalia in girls. Current treatment involves medication 3-4 times per day which has side effects, is difficult to accurately monitor and may not prevent negative health consequences. This project seeks to develop a permanent cure by repairing the faulty gene. The adrenal gland constantly renews itself so for gene therapy to be durable, the cells that re-populate the gland must be targeted. To do this, the gene therapy must be delivered to the right cells and location in the gland. Gene therapy can be delivered using a modified virus known as recombinant adeno associated virus (rAAV) and sometimes also uses lipid nanoparticles (LNP) like those used in COVID-19 vaccinations. This project will identify the most efficient type of gene delivery to the adrenal gland and develop a strategy to permanently repair the faulty gene using a combination of rAAV and LNP.

Andreas Schedl, Université Côte d’Azur, iBV, Centre de Biochimie, Nice

“Adrenocortical cells and organoids derived from human IPSCs“, 150000 Euros for 3 years

Congenital Adrenal Hyperplasia (CAH) is a severe disease caused by abnormal adrenal hormone production. At present, treatment of patients relies on hormone replacement therapy, which however causes severe side effects. An attractive alternative would be to transplant ‘repaired’ adrenal stem cells in which gene mutations have been corrected. Such a treatment could in principle represent a real cure for CAH patients. In the present project we will develop protocols that allow the generation of human adrenal cells. We will perform transplantation experiments to test whether the cells survive and produce hormones in a model system. This study will thus provide a proof of principle for future clinical applications.