Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochrome P450 21-hydroxylase into the adrenal gland of 21-hydroxylase-deficient mice

21-Hydroxylase deficiency, a potentially fatal disease due to deletions or mutations of the cytochrome P450 21-hydroxylase gene (CYP21), causes congen ital adrenal hyperplasia (CAH) with low or absent glucocorticoid and minera locorticoid production. The feasibility of gene therapy for CAH was studied using 21OH-deficient mice (21OH-) and a replication-deficient adenovirus c ontaining the genomic sequence of human CYP21 (hAdCYP21). Intra-adrenal inj ection of hAdCYP21 in 21OH- mice induced hCYP21 mRNA with the highest expre ssion from 2 to 7 days before a gradual decline. 21OH activity measured in adrenal tissue increased from undetectable to levels found in wild-type mic e 2 to 7 days after AdhCYP21 injection. Adrenal morphology of 21OH- mice sh owed lack of zonation, and hypertropy and hyperplasia of adrenocortical mit ochondria with few tubulovesicular christae. These morphological abnormalit ies were markedly improved 7 days after hAdCYP21 gene therapy. Plasma corti costerone increased from undetectable levels to values similar in wild-type mice 7 and 14 days, declining over the next 40 days. This is the first dem onstration that a single intra-adrenal injection of an adenoviral vector en coding CYP21 can compensate for the biochemical, endocrine and histological alterations in 21OH-deficient mice, and shows that gene therapy could be a feasible option for treatment of CAH.