Prenatal treatment of CAH – Long-term outcome with emphasis on metabolic, cognitive and epigenetic markers.

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 (DEX) supresses the fetal adrenal and reduces the production of adrenal androgens minimizing the viriliation of female fetuses. There is however an ethical dilemma, since the treatment with DEX has to be initiated early in gestation, already before the sex and the genotype of the fetus has been confirmed with chorionic villous sampling. 7 out of 8 fetuses (boys and healthy fetuses) are thus treated during early gestation (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 young adult age. Longitudinal growth, metabolic status, cognitive outcome and structural/functional MRI of the brain are evaluated. The effect on epigenetic changes in the genome is also addressed as a marker of fetal programming effects. In Sweden, about 70 cases have been treated since 1985, and the treatment has been performed in the frame of a clinical trial since 1999. We aim to finally evaluate this experimental treatment to be able to conclude whether we can accept further use in the clinical management of CAH. In addition, the study will lead to new knowledge how prenatal glucocorticoids affect early fetal programming and potential effects on future metabolic disease and human behaviour.

Investigator: Dr Svetlana Lajic, Stockholm, Sueden.

Funding: 95,000 €

Gene therapy for Congenital Adrenal Hyperplasia using administration of recombinant AAV vector encoding human CYP21

In the most severe form of 21-OHase deficiency affecting females, impaired synthesis of cortisol and aldosterone induces super active ACTH production that stimulates the excessive synthesis of 17-OH progesterone that causes marked androgen production and intra-uterine masculinization. At birth these baby girls show complete sexual ambiguity, external genitalia looking like those of a boy. After surgical correction and despite careful medical treatment, the girl’s body and genitalia remain exposed to lifelong and severe chronic virilization that results in a major restriction of sexual and marital life in adulthood justifying new therapeutic intervention, potentially including gene therapy. This project aims at developing a gene therapy approach based on intra-adrenal injection of a viral vector expressing the normal gene in order to correct the symptoms linked to the gene mutation in patients. Following proof of concept with 21-OHase deficient mice, the researchers selected the viral vector which has the better tropism for adrenal cortex. This project aims at evaluating the efficacy of the process in mice and performing feasibility studies in non-human primates.

Investigators M  Perdomini et P Bougnères, Le Kremlin_Bicêtre, France

Funding through partnership with AFM:76.500€