Extra-adrenal induction of Cyp21a1 ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia.

Abstract:

:Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase (21-OH) deficiency (21-OHD) is an autosomal recessive disorder, in which CYP21A2 mutations or deletions result in underproduction of glucocorticoid and mineralocorticoid, and overproduction of androgens. Patients with CAH are treated with oral steroid supplementation, but optimal control of blood steroid levels remains difficult. Thus, new therapeutic approaches are still needed. Previously, adenovirus-mediated administration of human CYP21A2 to adrenal glands rescued the phenotype of a mouse model of 21-OHD. In this study, we examined whether transduction of murine Cyp21a1 in extra-adrenal tissues could rescue steroid metabolism in 21-OHD mice. We transduced primary fibroblasts obtained from 21-OHD mice with a retroviral vector containing Cyp21a1. In vitro assays demonstrated that Cyp21a1-expressing fibroblasts can uptake progesterone from the culture media, convert it to deoxycorticosterone (DOC), and subsequently release DOC back into the media. Autotransplantation of Cyp21a1-expressing fibroblasts into the subcutaneous tissues of the back resulted in a significant reduction in the serum progesterone/DOC ratio in four of six 21-OHD mice at 4 weeks after injection. We also directly injected an adeno-associated viral vector containing Cyp21a1 into the thigh muscles of 21-OHD mice. Serum progesterone/DOC ratios were markedly reduced in all four animals at 4 weeks after injection. These results indicate that extra-adrenal induction of Cyp21a1 ameliorates steroid metabolism in 21-OHD mice. This study suggests a novel therapeutic strategy for congenital adrenal hyperplasia, which warrants further investigations.

journal_name

Endocr J

journal_title

Endocrine journal

authors

Naiki Y,Miyado M,Horikawa R,Katsumata N,Onodera M,Pang S,Ogata T,Fukami M

doi

10.1507/endocrj.EJ16-0112

subject

Has Abstract

pub_date

2016-10-29 00:00:00

pages

897-904

issue

10

eissn

0918-8959

issn

1348-4540

journal_volume

63

pub_type

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