What is Congenital Adrenal Hyperplasia?
 

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive genetic disorders caused by defects in key enzymes involved in adrenal corticosteroid synthesis. The core feature is impaired cortisol synthesis, which through negative feedback mechanisms leads to compensatory increased secretion of adrenocorticotropic hormone (ACTH), stimulating adrenal cortical hyperplasia while causing abnormal accumulation of precursor substances such as androgens.
 

The incidence of CAH in newborns is approximately 1/10,000 to 1/20,000, with 21-hydroxylase deficiency (caused by CYP21A2 gene mutations) accounting for 90%-95% of all cases, making it the most common type.
 

Based on clinical severity, CAH is classified into classic (including salt-wasting and simple virilizing forms) and non-classic types. Typical symptoms include salt-wasting crisis in the neonatal period (vomiting, dehydration, electrolyte disturbances), virilization of external genitalia in females, pseudoprecocious puberty in males, accelerated growth but ultimately short stature.
 

Pathogenesis
 

The pathogenesis of CAH stems from enzyme defects in the adrenal cortical steroid hormone synthesis pathway.
 

Specifically, under normal physiological conditions, adrenal steroidogenesis begins with cholesterol entering the mitochondrial inner membrane mediated by steroidogenic acute regulatory protein (StAR), catalyzed by side-chain cleavage enzyme (CYP11A1) to produce pregnenolone. Subsequently, the synthesis pathway diverges according to cortical zone differentiation: in the zona glomerulosa, due to the absence of CYP17A1, pregnenolone is sequentially catalyzed by HSD3B2, CYP21A2, and CYP11B2 to generate aldosterone. In the zona fasciculata, CYP17A1 exerts 17α-hydroxylase activity, converting precursors to 17-hydroxyprogesterone (17-OHP), which is then processed by HSD3B2, CYP21A2, and CYP11B1 to produce cortisol. In the zona reticularis, the 17,20-lyase activity of CYP17A1 is significantly enhanced with the cooperation of cytochrome b5 (CYB5A), promoting the conversion of precursors to dehydroepiandrosterone (DHEA) and androstenedione, which subsequently generate androgens.
 

 

In the normal pathway described above, 21-hydroxylase deficiency (21-OHD), as the most common type of congenital adrenal hyperplasia (CAH), has its pathological core in severe impairment or absence of 21-hydroxylase activity due to CYP21A2 gene mutations. This enzyme is a key catalytic enzyme in the aldosterone and cortisol synthesis pathways, responsible for converting progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol. When 21-hydroxylase function is defective, these two downstream pathways are blocked, leading to significantly insufficient synthesis of cortisol and aldosterone. Hypocortisolemia subsequently removes negative feedback inhibition on the hypothalamic-pituitary axis, causing sustained hypersecretion of adrenocorticotropic hormone (ACTH), which stimulates compensatory adrenal cortical hyperplasia. Simultaneously, due to obstruction of normal metabolic pathways, large amounts of precursor substances (particularly 17-OHP) abnormally accumulate in the body. These accumulated precursors are shunted to the intact androgen synthesis pathway, where through multiple enzymatic reactions (including participation of enzymes like CYP17A1), they are converted to androstenedione and further metabolized to potent androgens such as testosterone, ultimately resulting in the characteristic clinical syndrome.
 

Gene Therapy
 

Gene Replacement Therapy: Utilizes adeno-associated virus (AAV) vectors to deliver functional CYP21A2 genes into the body, compensating for defective genes. Through intravenous or local injection, vectors deliver the gene to the adrenal glands or liver, achieving ectopic expression of 21-hydroxylase. Currently, AAV5-CYP21A2 (such as BBP-631) has entered Phase I/II clinical trials.
 

Gene Editing Therapy: Utilizes gene editing technologies to directly repair pathogenic CYP21A2 mutations in the patient's genome. Through in situ repair or safe harbor site integration, permanent restoration of gene function is achieved.
 

Mouse Models
 

CYP21A2 Knockout Mice: Complete knockout of the CYP21A2 gene, developing severe corticosterone deficiency (<10% of wild-type) within weeks after birth, with significantly elevated 17-OHP, early compensatory aldosterone elevation followed by salt-wasting, 3-5-fold adrenal hyperplasia, with most dying at 4-8 weeks, modeling human salt-wasting CAH.
 

CYP21A2-R484Q Mutant Mice: Carry the R484Q point mutation, with moderate corticosterone reduction (30-50%), 5-20-fold elevation of 17-OHP, mild adrenal hyperplasia (1.5-2.5-fold), surviving to adulthood but with growth retardation and reduced fertility in females, modeling simple virilizing CAH.
 

CYP21A2-I173N Mutant Mice: Carry the I173N mutation, with mild corticosterone reduction (50-70%), mildly elevated basal 17-OHP that becomes significantly abnormal after ACTH stimulation, no significant adrenal hyperplasia, normal survival, modeling non-classic CAH or carrier phenotype.
 

MingCeler Biotech Supports Rare Disease Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation critically depend on animal model support. MingCeler Biotech has developed multiple rare disease mouse models using its proprietary TurboMice™ technology. The TurboMice™ platform overcomes technical challenges associated with long mouse model generation cycles and low success rates for complex models, enabling editing at virtually any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.
 

References:
 

1、https://www.ncbi.nlm.nih.gov/books/NBK448098/

2、Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2015 Jun;44(2):275-96. doi: 10.1016/j.ecl.2015.02.002. PMID: 26038201; PMCID: PMC4506691.

3、Graves LE, Christina S, Mullany KL, Alexander IE, Falhammar H. Exploration of the potential of genomic editing in the treatment of congenital adrenal hyperplasia. Front Endocrinol (Lausanne). 2025 Dec 10;16:1719376. doi: 10.3389/fendo.2025.1719376. PMID: 41450580; PMCID: PMC12728238.

4、Thirumalasetty SR, Schubert T, Naumann R, Reichardt I, Rohm ML, Landgraf D, Gembardt F, Peitzsch M, Hartmann MF, Sarov M, Wudy SA, Reisch N, Huebner A, Koehler K. A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia-CYP21A2-R484Q Mutant Mouse. Int J Mol Sci. 2024 May 7;25(10):5062. doi: 10.3390/ijms25105062. PMID: 38791102; PMCID: PMC11120801.

 

MingCeler Biotech can customize various CAH mouse models according to client needs, including CYP21A2 knockout mice, CYP21A2-R484Q mutant mice, CYP21A2-I173N mutant mice, and others. We welcome inquiries from researchers!

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