Original Article

Gene Therapy (2017) 24, 275–281; doi:10.1038/gt.2017.10; published online 9 March 2017

An AAVrh10-CAG-CYP21-HA vector allows persistent correction of 21-hydroxylase deficiency in a Cyp21/ mouse model

M Perdomini1, C Dos Santos2, C Goumeaux1, V Blouin3 and P Bougnères1,4,5

  1. 1University Paris Saclay, Le Kremlin Bicêtre, France
  2. 2INSERM UMR 1169, Bicêtre Gregory Pincus, Le Kremlin Bicêtre, France
  3. 3Atlantic Gene Therapies, INSERM UMR 1089, Nantes University, CHU Nantes, Nantes, France
  4. 4Gene Therapy Design, Paris, France
  5. 5Pediatric Endocrinology, Bicêtre Hospital, Le Kremlin Bicêtre, France

Correspondence: Professor P Bougnères, Pediatric Endocrinology, Bicêtre Hospital, 80 rue du Général Leclerc, 94276, Le Kremlin Bicêtre, France E-mail: pierre.bougneres@inserm.fr

Received 24 November 2016; Revised 20 January 2017; Accepted 25 January 2017
Accepted article preview online 6 February 2017; Advance online publication 9 March 2017

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Abstract

The treatment of severe forms of 21-hydroxylase deficiency (21OHD) remains unsatisfactory in many respects. As a monogenic disease caused by loss-of-function mutations, 21OHD is a potential candidate for a gene therapy (GT) approach. The first step of GT is to demonstrate positive effects of the therapeutic vector in the Cyp21/ mouse model. Thus, we tested the adrenal tropism of an AAVrh10-CAG-GFP vector (‘GFP vector’) then attempted to correct the phenotypic and biochemical alterations in Cyp21/ mice using an AAVrh10-CAG-humanCYP21A2-HA vector (‘CYP21 vector’). Cyp21/ mice had decreased body mass, high progesterone (4 ×), impaired stress response, increased adrenal expression of genes involved in steroidogenesis or ACTH signaling. Following injection of the GFP vector, Cyp21/ mice showed abundant GFP expression in the adrenal cortex. Intravenous injection of the therapeutic CYP21 vector allowed 21OH expression in adrenal tissue, resulting in increased body weight and near normalization of urinary progesterone for more than 15 weeks, improved response to stress and restoration of near-normal expression of (several important genes) in the adrenal cortex. The adrenal tropism of AAVrh10 and the persistent correction of phenotypic and biochemical traits in Cyp21/ mice pave a first step on the way to GT of 21OHD in humans.