DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for methylcobalamin deficiency type cblE — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMethylcobalamin deficiency type cblE maps to a 3-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
approvedHydroxocobalaminApproved drug
Structures already discussed alongside methylcobalamin deficiency type cble in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
The surface-exposed lipo-protein of BtuG2 — Hydroxocobalamin has a real, experimentally solved structure in complex with this target (PDB 8BB0, 1.5 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 i2adrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8BB0 · 1.5 Å · ligand Hydroxocobalamin (I2A). Experimental structure, not a prediction.
What the evidence adds up to
In a 2004 study of 456 ambulatory patients evaluated for cobalamin deficiency, pretherapy cobalamin, methylmalonic acid, and homocysteine levels varied by 23%, 23%, and 17% respectively over two to six weeks. Among 95 evaluable patients, 37 showed a haematologic or neurologic response to pharmacologic doses of cobalamin, yet 54% of those responders had normal pretherapy cobalamin, 23% had normal methylmalonic acid, and 50% had normal homocysteine. If treatment had been limited to symptomatic patients with low or intermediate cobalamin and elevated metabolites, 63% of responders would have been missed. Of 25 non-responders, 45% had low cobalamin, 45% had high methylmalonic acid, and 43% had high homocysteine. The authors concluded that these markers fluctuate over time and neither predict nor preclude a cobalamin-responsive disorder.
A 2002 study of 23 older adults with serum cobalamin ≤221 pmol/L and methylmalonic acid >271 nmol/L tested three sequential daily oral doses of cobalamin for six weeks each: 25 µg, 100 µg, and 1,000 µg. The 25 µg and 100 µg doses lowered methylmalonic acid but did not normalise it in most subjects. The 1,000 µg daily dose was the most effective at normalising methylmalonic acid. Homocysteine was normalised in six of 11 subjects who had elevated pretreatment homocysteine with oral cobalamin alone, and in one subject when combined with a multivitamin. The authors concluded that most cobalamin-deficient older people require more than 100 µg of oral cobalamin to normalise serum methylmalonic acid.
A 2019 report on three adult siblings with late-onset cobalamin C deficiency described a 28-year-old proband who presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis with pulmonary embolism. Standard-dose hydroxocobalamin (1 mg/day) initially gave only partial metabolic correction. A high-dose regimen of 25 mg/day hydroxocobalamin, together with betaine and folic acid, produced rapid and sustained biochemical correction, resolution of psychosis, improvement in neurological function, and amelioration of brain and spinal cord lesions seen on MRI. Two asymptomatic siblings achieved satisfactory metabolic control with the same high-dose regimen. Hydroxocobalamin injections were later spaced to 25 mg weekly with good metabolic control. All three patients were compound heterozygotes for c.271dupA and c.389A>G in MMACHC.
What remains missing is a systematic evaluation of optimal hydroxocobalamin dosing for adult patients with cobalamin C deficiency, as the 2019 report is limited to three siblings with the same genotype. The 2002 and 2004 studies address general cobalamin deficiency in older adults, not the specific inborn error cblE. No data exist on whether high-dose hydroxocobalamin would produce similar results in cblE deficiency, nor on the required trial design, patient stratification, or funding to test that question.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2004 · 159 citations · open access
Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing
AbstractEarly recognition of cobalamin (Cbl)-responsive disorders in the ambulatory care setting is essential to prevent irreversible neurologic deficits. However, diagnostic algorithms using Cbl, methylmalonic acid (MMA), and homocysteine (HCys) measurements reflect studies in academic centers, and their negative predictive values have not been established. Thus, records of 456 ambulatory patients evaluated for Cbl deficiency at a staff model HMO were reviewed. Pretherapy Cbl, MMA, and HCys values in individual patients varied by 23%, 23%, and 17%, respectively, over 2 to 6 weeks. Hematologic or neurologic responses to pharmacologic doses of Cbl occurred in 37 of the 95 evaluable patients. In these patients, pretherapy Cbl, MMA, and HCys values were normal in 54%, 23%, and 50%, respectively. If therapy had been restricted to symptomatic patients with both low or intermediate Cbl levels and increased metabolite values, 63% of responders would not have been treated. Twenty-five patients did not respond to treatment, including 5 of 11 patients (45%) with low Cbl, 22 of 49 patients (45%) with high MMA, and 13 of 30 patients (43%) with high HCys values. It is concluded that Cbl, MMA, and HCys levels fluctuate with time and neither predict nor preclude the presence of Cbl-responsive hematologic or neurologic disorders.
Journal of the American Geriatrics Society · 2002 · 89 citations
Response of Elevated Methylmalonic Acid to Three Dose Levels of Oral Cobalamin in Older Adults
AbstractOBJECTIVES: Because the effects of lower-dose oral cobalamin (Cbl) supplements on older people with cobalamin deficiency are not known, we determined whether oral Cbl supplements at three different dose levels would normalize elevated serum methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN: Sequential nonrandomized intervention study of three dose levels. SETTINGS: Two university-based senior care clinics. PARTICIPANTS: Twenty-three older adults (aged >/=65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum MMA greater than 271 nmol/L who had been enrolled in a previous screening study for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other). INTERVENTION: Sequential daily treatment with 25 microg oral cobalamin, followed by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS: Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing interval. RESULTS: Treatment with 25 microg and 100 microg lowered but did not normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be the most effective in lowering MMA levels to within normal limits. Serum tHcy was normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl alone and in one subject in combination with a multivitamin. CONCLUSIONS: Most Cbl-deficient older people require more than 100 microg of oral Cbl to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and Cbl supplements.
High‐dose hydroxocobalamin achieves biochemical correction and improvement of neuropsychiatric deficits in adults with late onset cobalamin C deficiency
AbstractAbstract Cobalamin C ( cblC ) deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in MMACHC and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late‐onset cblC may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late‐onset cblC disease, and their biochemical and clinical responses to high‐dose hydroxocobalamin. The 28‐year‐old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high‐dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high‐dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high‐dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late‐onset cblC disease.
Journal of Neurology and Experimental Neuroscience · 2016 · 1 citations · open access
Cobalamin C Deficiency: Case Report of Two Different Clinical Presentations
AbstractCobalamin C deficiency (CblC) is the most frequent inborn error of cobalamin (Cbl) metabolism, which has a wide clinical spectrum. Cbl C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. Here we presented two distinct clinical forms of patients with CblC. First patient with early onset form was presented with failure to thrive, mild hypotonia, megaloblastic anemia and leukopenia at 2.5 months old. Second patient was presented with mental status changes, loss of speech, inability to walk and megaloblastic anemia at 12 years old. Laboratory analysis showed hyperhomocysteinemia, low plasma methionine levels and high urinary methylmalonic acid in both patients. Molecular analysis supported the diagnosis of CblC and treatment resulted in improvement of biochemical abnormalities, and neurologic findings in both patients.
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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