DeCure for 3-hydroxyisobutyryl-CoA hydrolase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-hydroxyisobutyryl-CoA hydrolase deficiency — 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 module3-hydroxyisobutyryl-CoA hydrolase deficiency 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
No approved-drug candidate for 3-hydroxyisobutyryl-coa hydrolase deficiency 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
3-hydroxyisobutyryl-CoA hydrolase (HIBCH) — HIBCH 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 quedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3BPT · 1.5 Å · ligand 3,5,7,3',4'-PENTAHYDROXYFLAVONE (QUE). Experimental structure, not a prediction.
What the evidence adds up to
Only four cases of HIBCH deficiency had been reported by 2014. A study of two Japanese siblings carrying a new homozygous missense mutation (c.287C>A, p.A96D) at the substrate-binding site found that transfection experiments with four reported mutations (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13) revealed a correlation between residual enzyme activity and disease severity. The p.G317E mutant showed only about 3% of wild-type HIBCH activity. Although p.A96D had approximately seven times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. Only the patient with p.K74Lfs*13, which had no residual activity, had congenital anomalies.
A 2018 case report described a 1-year-6-month-old boy with developmental regression and paroxysmal dystonia after fever and diarrhoea, whose head MRI showed symmetrical lesions in the bilateral basal ganglia. No pathogenic mutation was found in the full-length mitochondrial genome, but nuclear gene testing revealed new compound heterozygous HIBCH mutations (c.439-2A>G and c.958A>G, p.K320E). He was given cocktail therapy, dietary valine restriction, and symptomatic treatment. After two weeks, there were improvements in dystonia and motor and intellectual development.
A 2019 report described an Iranian child presenting with developmental delay, Leigh-like MRI abnormalities, and elevated 3-hydroxyisovaleric acid. Whole-exome sequencing diagnosed HIBCH deficiency, and he was subjected to specific dietary treatment. The authors stated that HIBCH deficiency should be considered in the differential diagnosis of Leigh-like disease or organic aciduria.
What is still missing is any controlled trial of dietary valine restriction or cocktail therapy, any systematic comparison of these interventions against natural history, and any reliable biomarker that predicts which patients might respond. The evidence rests entirely on single case reports and small case series, with no standardised treatment protocol and no prospective data on long-term outcomes.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Genetics and Metabolism Reports · 2014 · 34 citations · open access
Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis
Abstract3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical-biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.
Clinical Case Reports · 2019 · 13 citations · open access
3‐Hydroxyisobutyryl‐CoA hydrolase deficiency in an Iranian child with novel <scp>HIBCH</scp> compound heterozygous mutations
AbstractWe report a patient presenting with developmental delay, Leigh-like abnormalities on MRI and elevated 3-hydroxyisovaleric acid levels. Upon whole-exome sequencing, he was diagnosed with 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, and hence subjected to specific dietary treatment. HIBCH deficiency should be considered in the differential diagnosis of Leigh-like disease and/or organic aciduria.
[Diagnosis and treatment of 3-hydroxyisobutyryl-CoA hydrolase deficiency: a case report and literature review].
AbstractA case of 3-hydroxyisobutyryl-CoA hydrolase deficiency was reported, and its clinical features, gene mutation characteristics, and diagnosis and treatment were analyzed with reference to related literature. The patient aged 1 year and 6 months had developmental regression and paroxysmal dystonia after pyrexia and diarrhea, and head MRI showed symmetrical lesions in the bilateral basal ganglia. No pathogenic mutation was found in the full-length detection of mitochondrial genome. Nuclear gene detection of mitochondrial-related diseases found new compound heterozygous mutations in the HIBCH gene, i.e., c.439-2A>G and c.958A>G (p.K320E), which were inherited from his father and mother, respectively. The boy was given cocktail therapy, dietary valine restriction, and symptomatic treatment. After 2 weeks of treatment, there were improvements in dystonia and motor and intellectual development.
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.
