AAV-delivered hepato-adrenal cooperativity in steroidogenesis: Implications for gene therapy for congenital adrenal hyperplasia

Lara E Graves; Eva B van Dijk; Erhua Zhu; Sundar Koyyalamudi; Tiffany Wotton; Dinah Sung; Shubha Srinivasan; Samantha L Ginn; Ian E Alexander

doi:10.1016/j.omtm.2024.101232

AAV-delivered hepato-adrenal cooperativity in steroidogenesis: Implications for gene therapy for congenital adrenal hyperplasia

Mol Ther Methods Clin Dev. 2024 Mar 12;32(2):101232. doi: 10.1016/j.omtm.2024.101232. eCollection 2024 Jun 13.

Authors

Lara E Graves^{1

2

3}, Eva B van Dijk¹, Erhua Zhu¹, Sundar Koyyalamudi^{2

3}, Tiffany Wotton⁴, Dinah Sung⁴, Shubha Srinivasan^{2

3}, Samantha L Ginn¹, Ian E Alexander^{1

2}

Affiliations

¹ Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia.
² Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia.
³ Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
⁴ NSW Newborn Screening Program, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.

Abstract

Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia; however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct in vivo gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalized, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.

Keywords: adeno-associated virus; congenital adrenal hyperplasia; gene addition; gene therapy; steroidogenesis.