DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for congenital adrenal hyperplasia — screening already-approved drugs against its 14-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 maps to a 14-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
approvedDexamethasoneApproved drug
Structures already discussed alongside congenital adrenal hyperplasia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of the agonist form of mouse glucocorticoid receptor stabilized by (A611V, F608S) mutations at 1.55A — Dexamethasone has a real, experimentally solved structure in complex with this target (PDB 3MNO, 1.55 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet dexdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3MNO · 1.55 Å · ligand Dexamethasone (DEX). Experimental structure, not a prediction.
What the evidence adds up to
In 38 children with classic 21-hydroxylase deficiency (25 salt-wasting, 13 simple virilising), plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower than in 39 age-matched normal subjects. The lowest values occurred in patients with the most severe deficits in cortisol production. Eight of the 38 patients (21 percent) had urinary epinephrine excretion and plasma epinephrine concentrations at or below the limit of detection. Among the CAH patients, those who had been hospitalised for adrenal crises had plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion approximately 50 percent lower than those who had not. In three CAH patients who underwent bilateral adrenalectomy, the adrenal medulla was incompletely formed and electron microscopy showed depletion of secretory vesicles in chromaffin cells. The study concluded that congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.
A 1977 review stated that after a generation of appropriately treated patients, most with congenital adrenal hyperplasia could lead virtually normal lives in terms of ultimate height and sexual development, with the key being early diagnosis. The review discussed the underlying biochemical mechanisms and the principles of adrenal hormone replacement therapy. A 2023 review noted that CAH is an autosomal recessive disease with an overall incidence of 1:9500–1:20,000 newborns. It stated that hormone replacement therapy does not address physiological requirements and that modern technologies make it possible to develop gene therapy drugs that could completely cure the disease. The review identified several promising drugs for CAH gene therapy but emphasised that no models for the disease exist, making it unclear how new approaches can be tested. It discussed the advantages and disadvantages of various pathological models and suggested ways of further development.
The 2000 study provides direct evidence of adrenomedullary dysfunction in CAH patients, with quantitative deficits in catecholamines and structural abnormalities in the adrenal medulla. The 2023 review highlights the absence of disease models as a barrier to testing gene therapies, despite the existence of candidate drugs. What remains missing is a validated animal or cellular model that recapitulates the human CAH phenotype, sufficient funding to develop such models, and clinical trial designs that can assess whether gene therapy or other interventions can restore normal adrenomedullary function alongside cortisol production.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2000 · 265 citations · open access
Adrenomedullary Dysplasia and Hypofunction in Patients with Classic 21-Hydroxylase Deficiency
AbstractBACKGROUND: Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. METHODS: We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. RESULTS: Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P<0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells. CONCLUSIONS: Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.
Diagnosis and Management of Congenital Adrenal Hyperplasia
AbstractAfter a generation of appropriately treated patients, it is now clear that most of those affected with congenital adrenal hyperplasia can lead virtually normal lives, in terms of ultimate height and sexual development. But the key is early diagnosis. The underlying biochemical mechanisms in the various forms of the disease are discussed, together with the principles and specifics of adrenal hormone replacement therapy.
AbstractPURPOSE OF REVIEW: To review the relevant publications since 2004 on surgery for female pseudohermaphroditism. Current controversies exist regarding the timing and technical aspects of female genital reconstruction and indeed the wisdom of performing these procedures in childhood. RECENT FINDINGS: Nine articles, published between 2004 and the present time, were found worthy of being included in this review. The topics include surgical technique, short-term and long-term results, voiding function after feminizing genitoplasty, and the timing of surgery. SUMMARY: Although results for surgery for congenital adrenal hyperplasia have been less than satisfactory when adults who had surgery in childhood are evaluated, all present reports include patients operated on using a variety of techniques many years ago. Rather than abandoning the efforts to repair this malformation early, we favor the continued development of more refined surgical techniques that may yield better results in the future.
International Journal of Molecular Sciences · 2023 · 7 citations · open access
Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing
AbstractThe adrenal glands are important endocrine organs that play a major role in the stress response. Some adrenal glands abnormalities are treated with hormone replacement therapy, which does not address physiological requirements. Modern technologies make it possible to develop gene therapy drugs that can completely cure diseases caused by mutations in specific genes. Congenital adrenal hyperplasia (CAH) is an example of such a potentially treatable monogenic disease. CAH is an autosomal recessive inherited disease with an overall incidence of 1:9500-1:20,000 newborns. To date, there are several promising drugs for CAH gene therapy. At the same time, it remains unclear how new approaches can be tested, as there are no models for this disease. The present review focuses on modern models for inherited adrenal gland insufficiency and their detailed characterization. In addition, the advantages and disadvantages of various pathological models are discussed, and ways of further development are suggested.
Management Approaches to Congenital Adrenal Hyperplasia in Adolescents and Adults; Latest Therapeutic Developments
AbstractThe main aim of the chapter entitled Management Approaches to Congenital Adrenal Hyperplasia (CAH) in Adolescents and Adults; Latest Therapeutic Developments, will be first to familiarize readers with current treatment guidelines using glucocorticoid and mineralocorticoid replacement in treating this common and under-diagnosed cause of amenorrhea. Next, to introduce readers to the concept of insulin resistance in CAH and treatment approaches based upon increasing insulin sensitivity. Finally, we shall consider possible future directions in the treatment of CAH.
Prenatal Diagnosis · 2024 · 7 citations · open access
Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up‐to‐date comprehensive review
AbstractCongenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.
The Medical Journal of Australia · 1974 · 3 citations
CONGENITAL ADRENAL HYPERPLASIA MANAGEMENT PROBLEMS IN THE TEENAGER*
AbstractA case of the simple virilizing form of congenital adrenal hyperplasia is reported in which adrenal suppression was lost while the patient was taking theoretically adequate doses of glucocorticoid. Even with dexamethasone in a dose of 8 m g daily, control of adrenal function, as indicated by some parameters, was not obtained within three days. That this is not an exceptional occurrence is illustrated by reference to a group of 17 other teenagers with congenital adrenal hyperplasia. A review of the literature indicates that an adrenal neoplasm, which might be suspected in such a situation, must be at most only a very remote possibility in such cases. It is suggested that when control deteriorates in this disorder it should be managed by giving an initial course of treatment at a high dosage level before returning to maintenance treatment at a dose only fractionally in excess of that being given previously.
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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