Among the 10 applications received, from France, Italy, Germany, Netherlands and UK, 3 projects were selected for funding.
Project 1 Etiological features of testicular adrenal rest tumors (TART) in patients with congenital adrenal hyperplasia (CAH)
In male CAH patients the development of testicular tumors (prevalence of up to 96%) may lead to gonadal dysfunction and infertility. These benign tumors show functional features of adrenocortical tissue. Therefore, they are called testicular adrenal rest tumors (TART).The etiology is not yet known. The nuclear receptor Ad4BP/SF-1 gene is important in the development of adrenocortical tissue. Overexpression of Ad4BP/SF-1 promotes increase in adrenocortical size and formation of ectopic adrenocortical tissue. We hypothesize that elevated ACTH and/or AII concentrations already in utero (as is the case in classic CAH) may lead to overexpression of Ad4BP/SF-1 and consequently proliferation/differentiation of primordial cells toward ectopic adrenal tissue within the fetal testes and expression of adrenal specific enzymes. Therefore, we will perform in vitro studies on the influence of chronic incubation of human fetal testes cells with ACTH and AII on the expression of adrenal specific enzymes and genes. Furthermore, we will evaluate hormonal control and gonadla function in CAH patients in more detail with special focus on periods of intermittently poor hormonal control as an etiological factor in the occurrence of TART by using our unique longitudinal CAH data base.
Investigator: Dr H Claahsen, Netherland, Funding 80.000€
Project 2: Discovery of pharmacological chaperones as novel treatment of congenital adrenal hyperplasia
Congenital adrenal hyperplasia due to 21-hydroxylase (CYP21A2) deficiency is one of the most common inborn conditions. Pharmaco-therapy remains suboptimal and requires optimisation. Current therapy is not tailored to the individual molecular genetic defects. The common p.I172N mutation, present in at least one third of CAH patients, affects protein stability. This makes this mutant a prime target for proteostasis network modification.
The proposed project will employ a truly translational approach by establishing zebrafish Cyp21a2 knock-out/-in models. After, crossbreeding these fish with a luciferase reporter strain, we will perform high-throughput in vivo compound screens for pharmacological chaperones to rescue mutant CYP21A2 activity in vivo.
Our in vivo approach will not only allow for identification of novel active compounds, but also fulfill criteria for toxicity screens. Ultimately, we will identify novel drug treatments for patients with CAH to improve long-term outcomes.
Investigator: Dr N Krone, UK. Funding 100.000€
Project 3 Prenatal treatment of CAH – Evaluation of treatment efficacy and long-term follow-up of treated children with emphasis on metabolic and neuropsychological outcome.
Prenatal treatment of CAH has been employed since the mid 1980´s, but long-term evaluation of this experimental treatment is scarce. In utero replacement with dexamethasone reduces the production of adrenal androgens that normally virilise the female CAH fetus. There is however an ethical dilemma, since the treatment with DEX has to be initiated early in gestation and 7 out of 8 fetuses (boys and healthy fetuses) are thus treated during the first trimester without any benefit of the treatment per se. CAH girls are treated during the entire gestational period.
The aim of the study is to evaluate treatment efficacy and to identify potential side-effects in the pregnant woman, the fetus and the growing child until adult age (18 y). Longitudinal growth, metabolic status and neuropsychological/cognitive outcome in conjunction with structural and functional MRI of the brain are evaluated. The effect on epigenetic changes in the genome in treated cases is also addressed.
In Sweden, about 80 cases have been treated since 1985, and the treatment has been performed in the frame of a clinical trial since 1999. In addition, we coordinate a European, multicentre, prospective study (PREDEX) to be able to finally evaluate this experimental treatment and to conclude whether we can accept further use of it in the clinical management of CAH.
The study will give information on how prenatal glucocorticoids affect early fetal programming and the potential effect on future metabolic disease and human behavior.
Investigator S Lajic, Sweden. Funding: 70.000€