Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice.
21-Hydroxylase deficiency, a potentially fatal disease due to deletions or mutations of the cytochrome P450 21-hydroxylase gene (CYP21), causes congenital adrenal hyperplasia (CAH) with low or absent glucocorticoid and mineralocorticoid production. The feasibility of gene therapy for CAH was studied using 21OH-deficient mice (21OH-) and a replication-deficient adenovirus containing the genomic sequence of human CYP21 (hAdCYP21). Intra-adrenal injection of hAdCYP21 in 21OH- mice induced hCYP21 mRNA with the highest expression from 2 to 7 days before a gradual decline. 21OH activity measured in adrenal tissue increased from undetectable to levels found in wild-type mice 2 to 7 days after AdhCYP21 injection. Adrenal morphology of 21OH- mice showed lack of zonation, and hypertrophy and hyperplasia of adrenocortical mitochondria with few tubulovesicular christae. These morphological abnormalities were markedly improved 7 days after hAdCYP21 gene therapy. Plasma corticosterone increased from undetectable levels to values similar in wild-type mice by 7 and 14 days, declining over the next 40 days. This is the first demonstration that a single intra-adrenal injection of an adenoviral vector encoding 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.
Tajima
T
T
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892-1862, USA.
Okada
T
T
Ma
X M
XM
Ramsey
W
W
Bornstein
S
S
Aguilera
G
G
D000256:Adenoviridae / Q000235:genetics*; D000311:Adrenal Glands / Q000201:enzymology*; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000235:genetics / Q000628:therapy*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D013255:Steroid 21-Hydroxylase / Q000187:drug effects* / Q000235:genetics; D014161:Transduction, Genetic
D013255:Steroid 21-Hydroxylase; D003345:Corticosterone