DeCure for Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCongenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for congenital adrenal hyperplasia due to cytochrome p450 oxidoreductase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
cytochrome p450 oxidoreductase (POR) — POR is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3QE2 · 1.75 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
A 2010 study of one adult patient with homozygous POR A287P mutation and her heterozygous mother used oral cocktail phenotyping to measure five major drug-metabolising CYP enzymes. Despite genotyping that predicted normal or high enzymatic activity, the patient showed subnormal activity of CYP1A2, CYP2C9, CYP2D6 and CYP3A4, and her mother showed subnormal activity of CYP1A2 and CYP2C9. The patient had received standard-dose oestrogen replacement from age 17 until 37, when it was stopped after she developed breast cancer. The authors concluded that in vivo assessment of drug metabolism should be considered in patients with PORD to tailor drug therapy and steroid replacement.
A 2023 review focused on 46,XX PORD patients notes that treatment may be complicated by adverse effects on drug metabolism caused by POR mutations. The review states that proper hormone replacement therapy can lead to decrease or resolution of ovarian macro-cysts, and that healthy babies have been delivered by in vitro fertilisation and frozen embryo transfer after adequate control of multiple hormonal imbalances. However, it also reports that delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity due to surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. Clinical outcomes and prognosis are influenced by specific POR mutations, additional genetic or environmental factors, and management, and range from early death to nearly normal phenotype with successful pregnancy.
A 2017 Chinese case report describes PORD as a rare disease with predominant signs including no puberty development, infantile reproductive organs, ear deformities, and bone synostosis in skull or limbs. A 2022 review of congenital adrenal hyperplasia generally lists negative long-term outcomes from multiple causes including supra-physiological glucocorticoid and mineralocorticoid replacement, excess adrenal androgens, and elevated steroid precursor and ACTH levels.
What is still missing are prospective studies with adequate sample sizes to establish clear treatment guidelines, standardised protocols for hormone replacement that account for the variable drug-metabolism impairment, and systematic long-term follow-up data on fertility outcomes and adrenal crisis prevention. No randomised trials exist, and no drug other than standard hormone replacement is mentioned in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Journal of Endocrinology · 2010 · 77 citations · open access
Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
AbstractOBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. DESIGN: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. METHODS: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. RESULTS: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. CONCLUSIONS: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.
Endocrinology and Metabolism · 2022 · 36 citations · open access
Long-Term Outcomes of Congenital Adrenal Hyperplasia
AbstractA plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco- and mineralocorticoid replacement, excess adrenal androgens both intrauterine and postnatal, elevated steroid precursor and adrenocorticotropic hormone levels, living with a congenital condition as well as the proximity of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene to other genes. This review aims to discuss the different long-term outcomes of CAH.
Journal of Clinical Medicine · 2023 · 4 citations · open access
Characteristics of Congenital Adrenal Hyperplasia Diagnosed in Adulthood: A Literature Review and Case Series
AbstractCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. CAH, depending on its clinical form, is usually diagnosed in the neonatal period, later in childhood, in adolescence, or in young adults. Herein, we report a case series of eight individuals in whom CAH was diagnosed between the ages of 18 and 81 years. Methods: We report on clinical presentations, hormonal tests, adrenal/gonadal imaging, and genetic findings. The clinical data of eight people with CAH, including four women (46, XX) and four men (46, XY), were reviewed. A genetic analysis of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene was performed in six patients. A comprehensive literature review was also conducted. Case series: Partial cortisol deficiency was found in all patients. The most frequent genotype was the homozygotic I173N mutation in CYP21A2. Adrenal masses were detected in seven patients, except for the youngest. Most of the patients were of short stature. Hypogonadotropic hypogonadism was detected in two males, and three females presented with primary amenorrhea. Hirsutism was noticeable in three females. All of the patients developed insulin resistance, and half of them were obese. Conclusions: The clinical presentations of different forms of CAH overlapped. Genotype–phenotype correlations were strong but not absolute. The management of CAH should be individualized and based on clinical and laboratory findings. Furthermore, the assessment of the cortisol response to adrenocorticotrophic hormone stimulation should be mandatory in all adults with CAH. Additionally, the regular long-term screening of cardiometabolic status is required in the CAH population.
Approach to the patient with cytochrome P450 oxidoreductase deficiency
AbstractCytochrome P450 oxidoreductase deficiency(PORD)is a rare disease, which is a subtype of congenital adrenal hyperplasia. The predominant signs include no puberty development, infantile reproductive organs, ear deformities, and bone synostosis in skull or limbs. Here, we analyzed the clinical features of a case with PORD confirmed by gene sequencing. The pathology, genetic features, clinical manifestations, diagnosis and treatment for PORD were reviewed. (Chin J Endocrinol Metab, 2017, 33: 68-71)
Key words:
P450 oxidoreductase deficiency; P450 oxidoreductase; Congenital adrenal hyperplasia; Skeletal malformations; 17α-hydroxyprogesterone
Table_1_Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.docx
Abstract<p>Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype–genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients’ outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.</p>
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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