DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal dominant hypocalcemia 1 — 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 moduleAutosomal dominant hypocalcemia 1 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 autosomal dominant hypocalcemia 1 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
calcium sensing receptor (CASR) — CASR 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 trpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7DTV · 3.5 Å · ligand TRYPTOPHAN (TRP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2010 study, five activating mutations of the calcium-sensing receptor (T151R, P221L, E767Q, G830S, A844T) from patients with autosomal dominant hypocalcemia 1 were expressed in HEK 293T cells. All patients had serum calcium between 1.7 and 2.0 mM with inappropriately low PTH and elevated urinary calcium. The mutant receptors showed exaggerated signalling, with EC50 values for extracellular calcium ranging from 1.56 to 3.15 mM, compared to 4.27 mM for wild-type. The calcilytic compound NPS-2143 reduced the responsiveness of four of the five mutants. The P221L mutant responded to NPS-2143 only when co-expressed with wild-type CaSR. The authors concluded that calcilytics might offer medical treatment for patients whose mutations are calcilytic-sensitive.
A 2006 case report described an infant with a de novo L727Q CaSR mutation who presented with hypocalcaemia at three weeks of age. The mutant receptor expressed in HEK 293 cells had a left-shifted dose-response curve (EC50 2.59 mM) compared to wild-type (3.78 mM). The child was treated with twice-daily recombinant human PTH(1-34) for 17 months. During that period, no further serious hypocalcaemic episodes occurred, and urinary calcium excretion declined remarkably. The authors recommended further evaluation of PTH as a treatment for autosomal dominant hypocalcaemia in young patients.
A 2006 Korean case report described a family with familial benign hypocalciuric hypercalcemia, not autosomal dominant hypocalcemia, carrying an E297K CaSR mutation. This is a separate disorder caused by inactivating rather than activating CaSR mutations. Two 2022 supplemental files from a case study and literature review on autosomal dominant hypocalcemia with a novel CASR mutation were provided but contained no extractable data.
What remains missing is a controlled clinical trial of either calcilytics or PTH in autosomal dominant hypocalcemia 1, with sufficient patient numbers and long-term follow-up to assess renal outcomes, as well as stratification by specific CaSR mutation to determine which mutants respond to calcilytic therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Clinical Endocrinology & Metabolism · 2010 · 59 citations
Novel Activating Mutations of the Calcium-Sensing Receptor: The Calcilytic NPS-2143 Mitigates Excessive Signal Transduction of Mutant Receptors
AbstractCONTEXT AND OBJECTIVE: Activating mutations in the calcium-sensing receptor (CaSR) gene cause autosomal dominant hypocalcemia (ADH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcilytic NPS-2143 on the signaling of mutant receptors as a potential new treatment for ADH patients. METHODS: Wild-type and mutant CaSR (T151R, P221L, E767Q, G830S, and A844T) were expressed in human embryonic kidney cells (HEK 293T). Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca(2+)](o)) in the presence or absence of NPS-2143. RESULTS: All ADH patients had lowered serum calcium ranging from 1.7 to 2.0 mm and inadequate intact PTH and urinary calcium excretion. In vitro testing of CaSR mutations from these patients revealed exaggerated [Ca(2+)](o)-induced cytosolic Ca(2+) responses with EC(50) values for [Ca(2+)](o) ranging from 1.56 to 3.15 mM, which was lower than for the wild-type receptor (4.27 mM). The calcilytic NPS-2143 diminished the responsiveness to [Ca(2+)](o) in the CaSR mutants T151R, E767Q, G830S, and A844T. The mutant P221L, however, was only responsive when coexpressed with the wild-type CaSR. CONCLUSION: Calcilytics might offer medical treatment for patients with autosomal dominant hypocalcemia caused by calcilytic-sensitive CaSR mutants.
The Journal of Clinical Endocrinology & Metabolism · 2006 · 54 citations · open access
A Hypocalcemic Child with a Novel Activating Mutation of the Calcium-Sensing Receptor Gene: Successful Treatment with Recombinant Human Parathyroid Hormone
AbstractCONTEXT: Persistent hypercalciuria, with the attendant risk of nephrocalcinosis and eventual renal failure, is common in hypoparathyroid patients, especially those with activating mutations of the calcium-sensing receptor (CASR) gene, being treated with oral calcium and calcitriol. Treatment with replacement PTH may be warranted, although this has yet to be evaluated in children. OBJECTIVES: The objectives of this study were to identify the cause of the disorder in a young hypocalcemic patient and to assess the efficacy of treatment of the patient with recombinant human PTH(1-34). SUBJECT: An infant presenting with hypocalcemia at 3 wk of age was studied. METHODS: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The patient was treated with twice-daily administration of recombinant human PTH(1-34) over a 17-month period. RESULTS: The proband was heterozygous for a de novo novel missense mutation (L727Q), on the border between transmembrane helix 4 and intracellular loop 2 of the CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve vs. that for the wild-type receptor [EC(50); mutant, 2.59 +/- 0.11 mm (mean +/- se) vs. wild-type, 3.78 +/- 0.12 mm, P < 0.001]. During treatment with PTH(1-34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably. CONCLUSION: PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients.
Yonsei Medical Journal · 2006 · 12 citations · open access
A Case Report of Familial Benign Hypocalciuric Hypercalcemia: A Mutation in the Calcium-Sensing Receptor Gene
AbstractFamilial benign hypocalciuric hypercalcemia (FBHH) is an autosomal dominant trait with high penetrance, clinically manifesting a relatively benign, lifelong, persistent hypercalcemia and hypocalciuria without hypercalcemic related complications. The calcium-sensing receptor (CaSR) plays an important role in the regulation of PTH secretion and calcium metabolism. Here we present a family with FBHH of an autosomal dominant inheritance. A heterozygous mutation of E297K (GAG --> AAG, exon 4) of CaSR gene was found in 3 family members. To our knowledge, it is the first confirmed case of FBHH with CaSR gene mutation in Korea.
sj-pdf-2-imr-10.1177_03000605221110489 - Supplemental material for Autosomal dominant hypocalcemia with a novel <i>CASR</i> mutation: a case study and literature review
AbstractSupplemental material, sj-pdf-2-imr-10.1177_03000605221110489 for Autosomal dominant hypocalcemia with a novel <i>CASR</i> mutation: a case study and literature review by Yingying Wu, Chao Zhang, Xiaojun Huang, Li Cao, Shihua Liu and Ping Zhong in Journal of International Medical Research
sj-pdf-1-imr-10.1177_03000605221110489 - Supplemental material for Autosomal dominant hypocalcemia with a novel <i>CASR</i> mutation: a case study and literature review
AbstractSupplemental material, sj-pdf-1-imr-10.1177_03000605221110489 for Autosomal dominant hypocalcemia with a novel <i>CASR</i> mutation: a case study and literature review by Yingying Wu, Chao Zhang, Xiaojun Huang, Li Cao, Shihua Liu and Ping Zhong in Journal of International Medical Research
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
