Biology of the Adrenal Gland Cortex Obviates Effective Use of Adeno-Associated Virus Vectors to Treat Hereditary Adrenal Disorders

Sandra Markmann, Bishnu P. De, Jasmine Reid, Clarisse L. Jose, Jonathan B. Rosenberg, Philip L. Leopold, Stephen M. Kaminsky, Dolan Sondhi, Odelya Pagovich, Ronald Crystal

Research output: Contribution to journalReview article

7 Citations (Scopus)

Abstract

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder occurring in 1:10,000 to 1:20,000 live births. In >95% of the cases, CAH results from mutations in the CYP21A2 gene, encoding the adrenal steroid enzyme 21-hydroxylase (21OH). Cardinal phenotypic features of CAH include genital ambiguity and sexual precocity, and in severe cases, neonatal salt loss and death. Current standard of care consists of lifelong oral steroid replacement to reverse the cortisol deficiency. Although significant advances in the treatment of CAH have been made, the burden of a lifelong therapeutic intervention is not ideal for quality of life. Gene therapy for CAH by adeno-associated virus (AAV) vectors has been shown to efficiently transduce the adrenal cortex, restoring normal steroidogenesis in the short term. However, adrenocortical cells are continuously renewed by stem cells located at the adrenal capsule, which differentiate as they centripetally migrate towards the adrenal medulla where they undergo apoptosis. In this context, we hypothesized that AAV-mediated genetic correction of the adrenal cortex will work short term but will eventually lead to a loss of correction. To test this hypothesis, we administered intravenously an AAV serotype rh.10 gene transfer vector (AAVrh.10-21OH-HA) to 21-hydroxylase deficient mice (21OH-/-). The data demonstrates that a single intravenous administration efficiently transduces adrenocortical cells leading to 21OH-HA expression and restoration of normal steroidogenesis. However, the duration of therapeutic efficacy lasted for only 8 weeks, accompanied by loss of 21OH-HA expression in the adrenal gland. Analysis in immunodeficient mice confirmed that the disappearance of transgene expression was not due to an antiviral/transgene immune response. Taken together, these results demonstrate that a single treatment with an adeno-associated viral vector expressing a functional copy of the mutated gene can only transiently treat adrenocortical hereditary disorders and that strategies to genetically modify the adrenocortical stem cells population will likely be required.

Original languageEnglish
Pages (from-to)403-412
Number of pages10
JournalHuman Gene Therapy
Volume29
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Fingerprint

Congenital Adrenal Hyperplasia
Dependovirus
Adrenal Cortex
Adrenal Glands
Steroid 21-Hydroxylase
Transgenes
Stem Cells
Genes
Disorders of Sex Development
Adrenal Medulla
Live Birth
Therapeutics
Standard of Care
Intravenous Administration
Genetic Therapy
Capsules
Antiviral Agents
Hydrocortisone
Salts
Steroids

Keywords

  • AAV vectors
  • adrenal gland
  • metabolic diseases
  • steroid metabolism

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Biology of the Adrenal Gland Cortex Obviates Effective Use of Adeno-Associated Virus Vectors to Treat Hereditary Adrenal Disorders. / Markmann, Sandra; De, Bishnu P.; Reid, Jasmine; Jose, Clarisse L.; Rosenberg, Jonathan B.; Leopold, Philip L.; Kaminsky, Stephen M.; Sondhi, Dolan; Pagovich, Odelya; Crystal, Ronald.

In: Human Gene Therapy, Vol. 29, No. 4, 01.04.2018, p. 403-412.

Research output: Contribution to journalReview article

Markmann, S, De, BP, Reid, J, Jose, CL, Rosenberg, JB, Leopold, PL, Kaminsky, SM, Sondhi, D, Pagovich, O & Crystal, R 2018, 'Biology of the Adrenal Gland Cortex Obviates Effective Use of Adeno-Associated Virus Vectors to Treat Hereditary Adrenal Disorders', Human Gene Therapy, vol. 29, no. 4, pp. 403-412. https://doi.org/10.1089/hum.2017.203
Markmann, Sandra ; De, Bishnu P. ; Reid, Jasmine ; Jose, Clarisse L. ; Rosenberg, Jonathan B. ; Leopold, Philip L. ; Kaminsky, Stephen M. ; Sondhi, Dolan ; Pagovich, Odelya ; Crystal, Ronald. / Biology of the Adrenal Gland Cortex Obviates Effective Use of Adeno-Associated Virus Vectors to Treat Hereditary Adrenal Disorders. In: Human Gene Therapy. 2018 ; Vol. 29, No. 4. pp. 403-412.
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abstract = "Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder occurring in 1:10,000 to 1:20,000 live births. In >95{\%} of the cases, CAH results from mutations in the CYP21A2 gene, encoding the adrenal steroid enzyme 21-hydroxylase (21OH). Cardinal phenotypic features of CAH include genital ambiguity and sexual precocity, and in severe cases, neonatal salt loss and death. Current standard of care consists of lifelong oral steroid replacement to reverse the cortisol deficiency. Although significant advances in the treatment of CAH have been made, the burden of a lifelong therapeutic intervention is not ideal for quality of life. Gene therapy for CAH by adeno-associated virus (AAV) vectors has been shown to efficiently transduce the adrenal cortex, restoring normal steroidogenesis in the short term. However, adrenocortical cells are continuously renewed by stem cells located at the adrenal capsule, which differentiate as they centripetally migrate towards the adrenal medulla where they undergo apoptosis. In this context, we hypothesized that AAV-mediated genetic correction of the adrenal cortex will work short term but will eventually lead to a loss of correction. To test this hypothesis, we administered intravenously an AAV serotype rh.10 gene transfer vector (AAVrh.10-21OH-HA) to 21-hydroxylase deficient mice (21OH-/-). The data demonstrates that a single intravenous administration efficiently transduces adrenocortical cells leading to 21OH-HA expression and restoration of normal steroidogenesis. However, the duration of therapeutic efficacy lasted for only 8 weeks, accompanied by loss of 21OH-HA expression in the adrenal gland. Analysis in immunodeficient mice confirmed that the disappearance of transgene expression was not due to an antiviral/transgene immune response. Taken together, these results demonstrate that a single treatment with an adeno-associated viral vector expressing a functional copy of the mutated gene can only transiently treat adrenocortical hereditary disorders and that strategies to genetically modify the adrenocortical stem cells population will likely be required.",
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