DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for mevalonic aciduria — 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 moduleMevalonic aciduria 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 mevalonic aciduria 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
mevalonate kinase (MVK) — MVK 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 2R3V · 2.5 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Mevalonic aciduria is caused by a deficiency of mevalonate kinase, the first enzyme after HMG-CoA reductase in the biosynthesis of cholesterol and nonsterol isoprenes. In a 1993 series of 11 patients, residual enzyme activity was virtually absent in all, yet clinical severity varied widely. The most severely affected patients had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, anaemia, diarrhoea and malabsorption, and died in infancy. Less severely affected patients had psychomotor retardation, hypotonia, myopathy, and ataxia. All 11 patients had recurrent crises with fever, lymphadenopathy, enlargement of liver and spleen, arthralgia, oedema, and a morbilliform rash. Neuroimaging showed selective and progressive cerebellar atrophy. Mevalonic acid concentrations were grossly elevated in body fluids. Plasma cholesterol was normal or only slightly reduced. Plasma ubiquinone-10 was decreased in most patients. Hypoglycaemia, metabolic acidosis, and lactic acidaemia were conspicuously absent.
A 2007 report described a 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment. He underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. Sustained remission of febrile attacks and inflammation was observed during a 15-month follow-up period. This is a single case, with no data on whether the underlying developmental or neurological features were altered.
A 1999 study identified four different missense mutations in mevalonate kinase cDNA from three patients, including three novel mutations. All mutations affected conserved amino acids. Heterologous expression of the mutant enzymes in E. coli showed a profound effect on enzyme activity. Immunoblot analysis of fibroblast lysates from patients detected virtually no mevalonate kinase protein, indicating the mutations affect both activity and stability of the protein.
What is still missing is any controlled trial of a treatment for mevalonic aciduria. The bone marrow transplant report is a single case with short follow-up and no control. No drug therapy has been shown to alter the course of the disease in a systematic study. Patient stratification by genotype or residual enzyme activity has not been linked to treatment response. Funding for natural history studies and for any interventional trial, even of repurposed agents, remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PEDIATRICS · 1993 · 291 citations
Clinical and Biochemical Phenotype in 11 Patients With Mevalonic Aciduria
AbstractOBJECTIVE: Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes. To establish the clinical and biochemical phenotype of mevalonic aciduria, the authors assembled their experience with 11 patients including attempts at therapeutic interventions. METHODS: Mevalonic acid in body fluids was determined by stable isotope dilution gas chromatography/mass spectroscopy with selected ion monitoring, ubiquinone-10 concentrations by reversed-phase high-pressure liquid chromatography. RESULTS: Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of the enzyme. The most severely affected patients have had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and have died in infancy. Less severely affected patients have had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients have had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. Mevalonic acid concentrations were found to be grossly elevated in body fluids of all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent. CONCLUSIONS: These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. It is concluded that although patients with mevalonic aciduria have a recognizable phenotype of serious clinical manifestations, some patients are likely to remain undiagnosed and may be found in a variety of subspecialty clinics, including neurology, gastroenterology, cardiology, and genetics.
New England Journal of Medicine · 2007 · 121 citations · open access
Allogeneic Bone Marrow Transplantation in Mevalonic Aciduria
AbstractMevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.
Identification and Characterization of Three Novel Missense Mutations in Mevalonate Kinase cDNA Causing Mevalonic Aciduria, a Disorder of Isoprene Biosynthesis
AbstractMevalonic aciduria is a rare autosomal recessive metabolic disorder, characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. The disorder is caused by a deficient activity of mevalonate kinase due to mutations in the encoding gene. Thus far, only two disease-causing mutations have been identified. We now report four different missense mutations including three novel ones, which were identified by sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria patients. All mutations affect conserved amino acids. Heterologous expression of the corresponding mutant mevalonate kinases as fusion proteins with glutathione S -transferase in Escherichia coli showed a profound effect of each of the mutations on enzyme activity. In addition, immunoblot analysis of fibroblast lysates from patients using specific antibodies against mevalonate kinase identified virtually no protein. These results demonstrate that the mutations affect not only the activity but also the stability of the mutant proteins.
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.
