2013

IFCAH received 25 applications from 11 different countries (France, UK, Germany, Netherland, Italy, Denmark, Romania, Belgium, Cyprus, Sweden, and Russia).

The Scientific committee selected 5 of them. Three are directly funded through IFCAH, while the 2 others are supported by an IFCAH partner, AFM (French association for muscular dystrophy), involved in developing genetic and cellular therapies of CAH.

Project 1: Characterisation of precursors of Testicular Adrenal Rest Tumours (TARTs) found in Congenital Adrenal Hyperplasia patients

Male patients with Congenital Adrenal Hyperplasia (CAH) exhibit a high prevalence of testicular adrenal rest tumours (TARTs) that can lead to gonadal damage and infertility in the adult. Data from human patients have indicated that TARTs start forming during fetal stages due to the high concentration of circulating ACTH, which is a feature of CAH. The origin and development of these tumours are poorly understood. Our studies on mouse testes have revealed the presence of dispersed interstitial cells expressing genes encoding adrenal specific steroidogenic markers. These cells have properties that led to the hypothesis that they represent precursors of mammalian TARTs. The aim of thisproject is to characterize the TART precursors in an effort to identify mechanisms that control TART development and growth, which will inform future targeted treatment in CAH patients. We will use ex vivo and in vivo whole organ approaches to determine the dependence of growth and adrenal marker expression of these precursors on ACTH and LH. Using genetic models and cell signaling inhibitors we will investigate the pathwaysthat are involved in TART development and growth.

Investigator : Dr A. Swain, London, UK. Funding : 115.000 €

Project 2: CAH beyond the age of 40 years. What challenges we face and what do we need to monitor?

Recent studies suggest serious long term health problems in patients with CAH including bone, cardiovascular and metabolic health. However, so far systematic data on comorbidities in a patient group with classic CAH at the age of 40 is lacking. In particular there is no data on cardiovascular morbidity in CAH as on young cohorts have been investigated so far. Many unresolved adverse clinical outcomes in CAH observed at an younger age have been attributed to side effects of chronic glucocorticoid (GC), hormonal imbalance and it has also been suggested that there might be an inherent increase risk of comorbidities. The current study will investigate the prevalence of an increased cardiovascular morbidity in 70 patients with classic CAH above the age of 40 and its underlying possible causes. We will investigate the correlation of cardiac outcome with GC treatment, disease severity, quality of disease control and TNXB haploinsufficiency.

Investigator : Dr N. Reisch, Munnich, Germany. Funding: 85.000 €

Project 3: Development of non-invasive prenatal diagnosis of CAH using cell free foetal DNA in the maternal circulation.

More than 90% of CAH cases are due to 21-hydroxylase deficiency, encoded by the CYP21A2 gene.Severe cases manifest as salt wasting, but can also result in virilisation of the external genitalia in affected female fetuses, an effect that can be ameliorated by maternal administration of dexamethasone before 9 weeks of pregnancy. Recent evidence suggest that this may adversely affect long term cognitive function, thus ideally, dexamethasone treatment should be targeted at the 1 in 8 mothers carrying an affected female fetus. Currently, definitive prenatal diagnosis of CAH requires asample of fetal material, obtained by chorionic villus sampling, which carries a 1% miscarriage risk and cannot be performed before 11 weeks gestation. Circulating cell-free fetal DNA (cffDNA) in maternal blood is an alternative source of genetic material that be tested from 6-7 weeks to determine fetal sex so that therapy can be targeted to female fetuses, but definitive diagnosis of affected fetuses still requires an invasive test.

This project proposes developing definite diagnosis of CAH using cffDNA to allow early targeted administration of dexamethasone to affected female fetuses.

Investigator : Dr L. Chitty, London, UK   Funding 50 000 €.

Project 4: Cell therapy for the treatment of CAH using an implantable medical device

Congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase is the most common endocrine genetic disorder in humans presenting with clinical symptoms of virilisation, neuroendocrine perturbations and metabolic disease in later life. Patients may suffer from hypotensive crises due to adrenal insufficiency, hypoglycaemia, acne and infertility. Current treatment options with glucocorticoid substitution can reverse these symptoms only partially and exhibit the unpleasant side effects of excess glucocorticoid treatment. Therefore, restoration of normal adrenal function by adrenal cell transplantation would be eminently suited to treat this common genetic disease. We use a novel implantable medical device, which successfully proved its ability to protect implanted tissue from isogenic, allogeneic and xenogeneic host immune systems. Here, we propose to employ this system in a subcutaneous location with immune-isolated bovine adrenal cells in adrenalectomized rats to restore a normal feedback regulation of the adrenal system. We believe that our system provides a promising therapeutic strategy for patients with CAH.

Investigator : Dr S. Bornstein,  Munnich, Germany. Funding : 76 462 €

Project 5: Combined cell and gene therapy as a novel approach for the treatment of human 21-hydroxylase-deficiency

Congenital adrenal hyperplasia due to 21-hydroxylase-deficiency is an autosomal-recessive disorder characterized by cortisol deficiency, aldosterone deficiency, and chronic stimulation of the adrenal by corticotropin and hyperandrogenism. Patients with such disease are compelled to life-long glucocorticoid replacement therapy to prevent death by cardiovascular collapsus. However, available treatment is far from ideal, and recent studies have pointed out excess mortality due to inappropriate glucocorticoid replacement therapy.

As a logical consequence from the current experiences, a treatment strategy that has fewer side effects and will correct the underlying genetic defect would be highly desirable. We are now proposing to develop a novel therapeutic approach based on an adrenal cell-based transplantation approach.  We are introducing the CYP21A2 gene into cells isolated from patients after unilateral adrenalectomy to restore the 21-hydroxylase activity prior autotransplantation. We will explore the feasibility of this approach by using the mouse model we developed and our expertise in genetically modification of adrenocortical cells.

Investigator : Dr M Thomas, Grenoble, France. Funding: 23 538€

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