ESPE Abstracts (2016) 86 FC1.5

AAV Gene Therapy of 21-Hydroxylase Deficiency (21OHD) in Cyp21−/− mice

Morgane Perdominia, Christine Menguy-Dos Santosa, Cyndie Goumeauxa, Sylvie Guidouxa, Guillaume Pourchera, Patrick Aubourga,b & Pierre Bougnèresb,c

aU1169INSERM, Bicêtre, France; bGene Therapy Design, Bicêtre, France; cPediatric Endocrinology, Bicêtre, France

Background: Despite current treatment, girls and women with severe forms of 21OHD are exposed lifelong to a chronic excess of androgens and the secondary effects of suppressive corticoids, which make gene therapy (GT) an option to be explored.

Objective: To evaluate the effect of human CYP21 gene transfer mediated by adeno-associated virus (AAV) in a Cyp21/ mouse model.

Methods: 17 adult Cyp21/ mice received two doses of AAVrh10- CYP21 vector. Wild type (WT) mice (n=9) and control untreated Cyp21−/− mice (n=7) were injected with a control vector. Weight and progesterone were measured for 15 weeks. At this date, vector copy number (VCN), qRTPCR of steroidogenic enzyme mRNAs and immunohistochemistry of adrenal cortexwere studied.

Results: GT of Cyp21/ mice resulted in a progressive and stable decrease of urinary progesterone, which became 19.5±6 ng/mg creatinine (vs 56±15 before treatment). For comparison, urinary progesterone is 7.5±3 in WT. Weight increased from 14.5±2 g to 25.5±1 g in males (normal 30) and from 16±1 g to 22.5±1.5 g for females (normal 25). Mean VCN was 0.1–0.15 per cell depending on vector dose. Immunohistochemistry showed CYP21 expression in both zona glomerulosa and fasciculata. Correction of hyperexpressed Star, Cyp17a1, Cyp11b2, Mc2r and PRKAR1A/R2A/Ca/Cb was observed in adrenals and of hyperexpressed renin in kidney.

Conclusion: Systemic GT at the studied doses allowed a near-complete correction of the Cyp21−/− phenotype. Studies in large animals are underway.

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