Project A04

In vitro and in vivo models of novel therapeutic approaches in congenital adrenal hyperplasia


Univ.-Prof. Dr. Nicole Reisch
nicole.reisch(at)med.uni-muenchen.de
Medizinische Klinik und Poliklinik IV
Endokrinologie, Diabetologie
Klinikum der Universität München


Prof. Dr. Angela Hübner
angela.huebner(at)uniklinikum-dresden.de
Kinder- und Jugendmedizin
Abt. Endokrinologie/Diabetologie
Universitätsklinikum Carl Gustav Carus Dresden


PD Dr. Katrin Köhler
katrin.koehler(at)uniklinikum-dresden.de
Klinik für Kinder- und Jugendmedizin
Molekulare Endokrinologie, Labor für Klinische Forschung
Universitätsklinikum Carl Gustav Carus Dresden

Scientific staff

Dr. med. Friederike Quitter, Clinician Scientist RISE
Dr. med. Matthias Auer, Clinician Scientist
Tina Schubert – PhD-Student

Project Description

The project A04 deals with the development of new treatments for Congenital Adrenal Hyperplasia (CAH) focusing on the therapeutic effect of MC2-receptor antagonists and pharmacological chaperones. For functional in vivo tests of novel therapeutic agents, a humanised CYP21A2-deficient mouse model has been developed and will be characterized. The existing paediatric and adult CAH databases will be combined into one longitudinal national database allowing for continuity, which will then represent an excellent database for translational CAH research.

Aims

(I) Develop improved antagonistic peptides suppressing the MC2R pathway
(II) Model and optimise pharmacological chaperones for rescuing CYP21A2 enzyme activity
(III) Characterise and utilise the CAH mouse model for in vivo tests of peptides and chaperones
(IV) Establish a national combined paediatric and adult CAH database

PhD/MD-Thesis

Tina Schubert: Novel therapeutic approaches for congenital adrenal hyperplasia (2017-2021)

Awards

2018 – Dietrich-Knorr Prize of the German Society for Paediatric Endocrinology and Diabetology (to Angela Hübner and Katrin Köhler)

Shamini Ramkumar Thirumalasetty: Characterization of a humanized CYP21A2 mouse model for Congenital Adrenal Hyperplasia (CAH)

Awards

2022 – Best Speaker Award of the 23rd Annual Meeting of Young Active Research in Endocrinology

Publications

Hoyer-Kuhn H, Huebner A, Richter-Unruh A, Bettendorf M, Rohrer T, Kapelari K, Riedl S, Mohnike K, Dörr HG, Roehl FW, Fink K, Holl RW, Woelfle J. Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: results of the German/Austrian registry. Endocr Connect. 2021;10:561-569.

Nowotny HF, Auer MK, Lottspeich C, Schmidt H, Dubinski I, Bidlingmaier M, Adaway J, Hawley J, Keevil B, Reisch N. Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2021:dgab446.

Auer MK, Gebert D, Biedermann SV, Bindila L, Stalla G, Reisch N, Kopczak A, Fuss J. Altered endocannabinoid-dynamics in craniopharyngioma patients and their association with HPA-axis disturbances. Eur J Endocrinol. 2021:EJE-21-0178.R1.

Auer MK, Paizoni L, Neuner M, Lottspeich C, Schmidt H, Bidlingmaier M, Hawley J, Keevil B, Reisch N. 11-oxygenated androgens and their relation to hypothalamus-pituitary-gonadal-axis disturbances in adults with congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2021;212:105921.

Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, White PC. Congenital adrenal hyperplasia – current insights in pathophysiology, diagnostics and management. Endocr Rev. 2021:bnab016.

Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ. Modified-release hydrocortisone in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2021;106:e2063-e2077.

Nowotny H, Ahmed SF, Bensing S, Beun JG, Brösamle M, Chifu I, Claahsen van der Grinten H, Clemente M, Falhammar H, Hahner S, Husebye E, Kristensen J, Loli P, Lajic S, Reisch N; Endo ERN (MTG1). Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis. Endocrine. 2021;71:586-594.

Claahsen-van der Grinten HL, Stikkelbroeck N, Falhammar H, Reisch N. Management of endocrine disease: Gonadal dysfunction in congenital adrenal hyperplasia. Eur J Endocrinol. 2021;184:R85-R97.

Verhees MJM, Engels M, Span PN, Sweep FCGJ, van Herwaarden AE, Falhammar H, Nordenström A, Webb EA, Richter-Unruh A, Bouvattier C, de la Perrière AB, Arlt W, Reisch N, Köhler B, Rapp M, Stikkelbroeck NMML, Roeleveld N, Claahsen-van der Grinten HL. Quality of life in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Front Endocrinol (Lausanne). 2021;12:626646.

Auer MK, Paizoni L, Hofbauer LC, Rauner M, Chen Y, Schmidt H, Hübner A, Bidlingmaier M, Reisch N. Effects of androgen excess and glucocorticoid exposure on bone health in adult patients with 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2020;105734

Reisch N. Review of health problems in adult patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes. 2019;127:171–177

Koehler K, Hmida D, Schlossmann J, Landgraf D, Reisch N, Schuelke M, Huebner A. Homozygous mutation in murine retrovirus integration site 1 gene associated with a non-syndromic form of isolated familial achalasia. Neurogastroenterol Motil. 2020;e13923

Koehler K, Hackmann K, Landgraf D, Schubert T, Shakiba M, Kariminejad A, Huebner A. Homozygous deletion of the entire AAAS gene in a triple A syndrome patient. Eur J Med Genet. 2019;62:103665

Lottspeich C, Müller-Lisse U, Seiler L, Schmitt-Graeff AH, Reincke M, Reisch N. Three Cases of Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia-A Diagnostic and Therapeutic Challenge. Urology. 2019;129:24–28

Paizoni L, Auer MK, Schmidt H, Hübner A, Bidlingmaier M, Reisch N. Effect of androgen excess and glucocorticoid exposure on metabolic risk profiles in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2020;197:105540.

Reisch N. Pregnancy in Congenital Adrenal Hyperplasia. Endocrinol Metab Clin North Am. 2019;48:619–641

Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, Krone N, Auchus RJ, Shackleton CHL, Hanley NA, Arlt W. Alternative pathway androgen biosynthesis and human fetal female virilization. Proc Natl Acad Sci USA. 2019;116:22294–22299

Auer M, Krumbholz A, Bidlingmaier M, Thieme D, Reisch N. Steroid 17-hydroxyprogesterone in hair is a potential long-term biomarker of androgen control in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Neuroendocrinology. 2019. doi:10.1159/000504672