DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for primary aldosteronism — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePrimary aldosteronism maps to a 6-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 primary aldosteronism 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
T-box transcription factor 3 (TBX3) — TBX3 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1H6F · 1.7 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a prospective study of 54 patients with primary aldosteronism followed for a mean of 7.4 years after adrenalectomy or spironolactone, baseline cardiovascular event prevalence was 35% in primary aldosteronism versus 11% in essential hypertension (odds ratio 4.61). After treatment, blood pressure was comparable between groups, and the combined cardiovascular end point (myocardial infarction, stroke, revascularisation, sustained arrhythmias) occurred in 10 primary aldosteronism patients and 19 essential hypertension patients (P = 0.85). Cardiovascular outcome did not differ between surgical and medical treatment (P = 0.71). Older age and longer hypertension duration were independently associated with the end point.
Primary aldosteronism affects 6–13% of hypertensive patients. Aldosterone-producing adenomas carry somatic mutations in KCNJ5 at a prevalence above 40% worldwide. Other mutated genes in these adenomas include ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H, and ARMC5. Germline KCNJ5 mutations cause familial bilateral primary aldosteronism with variable severity. Somatic KCNJ5 mutations in adenomas are associated with younger age, female sex, more severe aldosteronism, lack of aldosterone response to upright posture, and zona fasciculata histology. The two most common mutations are G151R and L168R. These mutations reduce potassium/sodium channel selectivity, causing sodium influx, membrane depolarisation, calcium influx, and increased aldosterone synthesis gene expression. How they drive cell proliferation and tumour development is less well understood.
Familial hyperaldosteronism types I–IV are rare. The sporadic forms—unilateral adenoma or bilateral hyperplasia—predominate. Gene expression profiling of adenomas has identified intracellular signalling pathways possibly involved in pathogenesis. Compared with essential hypertension, primary aldosteronism patients have a higher incidence of target organ damage and cardiovascular events. The molecular mechanisms of familial hyperaldosteronism type I are understood, but those of other subtypes remain under investigation.
What is still missing: prospective trials large enough to detect whether specific mutation profiles predict differential response to surgery versus medical therapy; validated biomarkers to stratify patients by cardiovascular risk beyond blood pressure control; and funding for genomic screening in routine diagnostic pathways to move beyond the current reliance on adenoma resection or non-targeted aldosterone blockade.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Internal Medicine · 2008 · 560 citations · open access
Cardiovascular Outcomes in Patients With Primary Aldosteronism After Treatment
AbstractBACKGROUND: Experimental and human studies demonstrate that long-term exposure to elevated aldosterone levels results in cardiac and vascular damage. METHODS: We investigated long-term cardiovascular outcomes in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with or without evidence of adrenal adenomas were prospectively followed up for a mean of 7.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with patients with essential hypertension and were treated to reach a blood pressure of less than 140/90 mm Hg. The main outcome measure was a combined cardiovascular end point comprising myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias. RESULTS: At baseline, the prevalence of cardiovascular events was greater in primary aldosteronism (35%) than in essential hypertension (11%) (odds ratio, 4.61; 95% confidence interval, 2.38-8.95; P< .001), with odds ratios of 4.93, 4.36, and 2.80 for sustained arrhythmias, cerebrovascular events, and coronary heart disease, respectively. Blood pressure during follow-up was comparable in the primary aldosteronism and essential hypertension groups. Ten patients in the primary aldosteronism group and 19 in the essential hypertension group reached the primary end point (P= .85). Cox analysis indicated that older age and longer duration of hypertension were factors independently associated with the cardiovascular end point. Cardiovascular outcome was comparable in patients with aldosteronism treated with adrenalectomy vs aldosterone antagonists (P= .71). CONCLUSION: Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.
Endocrine Related Cancer · 2016 · 33 citations · open access
Genetics of primary hyperaldosteronism
AbstractHypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5 This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.
International Journal of Molecular Sciences · 2018 · 15 citations · open access
Comparative Genomics and Transcriptome Profiling in Primary Aldosteronism
AbstractPrimary aldosteronism is the most common form of endocrine hypertension with a prevalence of 6% in the general population with hypertension. The genetic basis of the four familial forms of primary aldosteronism (familial hyperaldosteronism FH types I–IV) and the majority of sporadic unilateral aldosterone-producing adenomas has now been resolved. Familial forms of hyperaldosteronism are, however, rare. The sporadic forms of the disease prevail and these are usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Aldosterone-producing adenomas frequently carry a causative somatic mutation in either of a number of genes with the KCNJ5 gene, encoding an inwardly rectifying potassium channel, a recurrent target harboring mutations at a prevalence of more than 40% worldwide. Other than genetic variations, gene expression profiling of aldosterone-producing adenomas has shed light on the genes and intracellular signalling pathways that may play a role in the pathogenesis and pathophysiology of these tumors.
Current Opinion in Endocrinology Diabetes and Obesity · 2013 · 7 citations
Primary aldosteronism and potassium channel mutations
AbstractPURPOSE OF REVIEW: To summarize and discuss data from recent studies implicating mutations in potassium channel genes in the pathogenesis of primary aldosteronism. RECENT FINDINGS: Potassium channel gene variants are associated with the primary aldosteronism phenotype in animals (Kcnma1, TASK-1, and TASK-3) and humans (HERG and KCNJ5). Germline KCNJ5 mutations cause bilateral, familial primary aldosteronism with variable severity and genotype:phenotype correlations. Somatic KCNJ5 mutations occur in approximately 40% of aldosterone-producing adenomas, and are associated with younger age, female sex, more severe primary aldosteronism, lack of responsiveness of plasma aldosterone to upright posture, and zona fasciculata histology. Of five so far described, G151R and L168R are by far the most common. KCNJ5 mutations lead to reduced K⁺/Na⁺ channel selectivity and Na⁺ influx, predisposing to cell membrane depolarization, increased calcium influx, increased expression of genes promoting aldosterone synthesis, and increased aldosterone production by adrenocortical cells. How they lead to adrenal cell proliferation and tumor development is less well understood. SUMMARY: These findings shed considerable light on the pathophysiology of primary aldosteronism with the potential to lead to new diagnostic approaches and treatments.
AbstractPrimary aldosteronism (PA) is one of the common forms of secondary hypertension.Compared with essential hypertension patients,PA patients have a higher incidence of target organ damage and cardiovascular events.Elucidation of the underlying molecular mechanisms will likely aid the development of targeted treatments and improve prognosis for PA patients.At present,studies have elucidated the pathogenesis of familial hyperaldosteronism type Ⅰ,while the study of the pathogenesis of other subtypes is still in progressing.This review introduces the current studies on the molecular genetics of primary aldosteronism.
Key words:
Primary aldosteronism ; Pathogenesis ; Aldosterone synthase ; KCNJ5
American Journal of Clinical Pathology · 1970 · 0 citations
Clinical Manifestations of Primary Aldosteronism
AbstractJournal Article Clinical Manifestations of Primary Aldosteronism Get access David R. Rovner, M.D. David R. Rovner, M.D. Division of Endrocrinology and Metabolism, Department of Internal Medicine, University Hospital, Ann Arbor, Michigan 48104 Search for other works by this author on: Oxford Academic Google Scholar American Journal of Clinical Pathology, Volume 54, Issue 3, 1 September 1970, Pages 314–315, https://doi.org/10.1093/ajcp/54.3.314 Published: 01 September 1970 Article history Received: 20 January 1970 Accepted: 05 March 1970 Published: 01 September 1970
Journal of the Endocrine Society · 2021 · 0 citations · open access
“Relieving the Pressure” With Unilateral Adrenalectomy in a Case of Chronic Resistant Hypertension From Primary Aldosteronism
AbstractAbstract Introduction: Primary aldosteronism is an under-recognized cause of resistant hypertension that is associated with an increased risk of cardiovascular disease and mortality. While surgical intervention may not lead to complete resolution of hypertension, partial success (defined by reduction in blood pressure and/or medications) can be achieved and future cardiovascular risks can be minimized. We present a case of a patient with primary aldosteronism whose chronic resistant hypertension improved significantly after unilateral adrenalectomy. Clinical Case: A 54-year-old female with resistant hypertension for 17 years and hypokalemia was diagnosed with primary aldosteronism. The patient had uncontrolled hypertension despite atenolol 50 mg, nifedipine XL 60 mg, triamterene-hydrochlorothiazide 37.5-25 mg, lisinopril 40 mg daily. Laboratory evaluation was significant for plasma aldosterone concentration (PAC) 26.8 ng/dL (reference: 0.0–30.0 ng/dL), plasma renin activity (PRA) 0.168 ng/mL/hr (reference: 0.167–5.380 ng/mL/hr), PAC/PRA ratio 159.5, and potassium of 3.2 mmol/L (reference: 3.5–4.5mmol/L). Other workup showed plasma normetanephrines 128 pg/mL (reference: 0–145 pg/mL), metanephrines 25 pg/mL (reference: 0–62 pg/mL), and two normal midnight salivary cortisol tests. Saline infusion testing confirmed primary aldosteronism with a non-suppressed aldosterone level of 15.6 ng/dL (normal &lt;5 ng/dL). Abdominal imaging revealed two low-density right adrenal nodules consistent with adenomas and thickening of the left adrenal gland. The patient underwent adrenal vein sampling (AVS) with cosyntropin stimulation, which showed lateralization to the right adrenal. Despite adding clonidine 0.1 mg three times daily, hydralazine 25 mg three times daily and spironolactone 100 mg daily (which substituted triamterene-hydrochlorothiazide) after AVS, her blood pressure remained uncontrolled with blood pressure ranging from 150–180/90–110 mmHg. A laparoscopic right adrenalectomy was performed. Pathology revealed two adrenal cortical adenomas. At the one-month post-operative visit, her potassium was normal, PAC was 4.3 ng/dL, and blood pressure improved on a reduced regimen of atenolol, lisinopril, and nifedipine. Conclusion: In patients with chronic uncontrolled hypertension due to primary aldosteronism, surgical intervention may not lead to complete resolution of hypertension but may lead to partial clinical success. Residual hypertension may be due to underlying vascular changes associated with long-term exposure to elevated aldosterone. The post-operative PAC in our case was less than 5 ng/dL suggesting biochemical cure and potentially reduced cardiovascular risk. This case emphasizes that adrenalectomy should be considered in resistant hypertension, even if complete clinical cure may not be attainable to reduce future cardiovascular events.
Aldosteronoma causing Conn’s syndrome: a case report and literature review
AbstractWe report a case of primary aldosteronism caused by bilateral solitary aldosteronomas occurring 6 months apart, the diagnosis being confirmed by clinical features. Multiple aldos-terone-producing adenomas can be unilateral or bilateral. If bilateral, most of them are found simultaneously. Bilateral solitary aldosterono-mas occurring at separate times are rarely re-ported and the pathogenesis is still elusive. We believe, from this case, the postoperative fol-low-up in patients with primary aldosteronism is mandatory.
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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