DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hypobetalipoproteinemia — 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 moduleHypobetalipoproteinemia 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 hypobetalipoproteinemia 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.
What the evidence adds up to
People with LDL cholesterol at or below the fifth percentile of the population (roughly 90 mg/dL in Western populations) are defined as having hypobetalipoproteinemia. Epidemiological studies show these individuals have a lower-than-average risk of atherosclerotic cardiovascular disease but a higher risk of a variety of cancers, pulmonary diseases, and gastrointestinal diseases compared to people with higher cholesterol. The reasons for this are not known, nor are the causes of most cases of hypobetalipoproteinemia.
In some well-studied families the condition is inherited as an autosomal dominant trait. Heterozygotes in such families are usually healthy and have no difficulty absorbing dietary fat. In a subset of these families, the low-cholesterol phenotype is linked to truncation-producing mutations of the apolipoprotein B-100 gene. Twenty-five truncations had been identified by 1995, named apoB-2 through apoB-89. These mutations slow the secretion of the truncated apoB proteins and also slow the secretion of the normal apoB-100 molecules in heterozygotes compared to matched normolipidemic controls. The response of these heterozygotes’ plasma lipoproteins to dietary manipulation remains to be determined.
Additional low-cholesterol syndromes include autosomal recessive forms of hypobetalipoproteinemia, chylomicron retention disease, and abetalipoproteinemia. The molecular causes of the first two were unknown in 1995. Abetalipoproteinemia is an autosomal recessive condition caused by mutations of the microsomal triglyceride transfer protein. All three conditions are characterised by vanishingly small LDL concentrations, dietary fat malabsorption, and failure to thrive in infancy. A 2022 report of a paediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant lists clinical manifestations including malabsorption, nonalcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and haematological dysfunction.
What is still missing is a clear understanding of the mechanisms linking low LDL to the observed higher risks of cancer and other diseases, the molecular causes of most hypobetalipoproteinemia cases, and the dietary or therapeutic management of affected patients. No randomised trials or systematic treatment studies have been reported for this population.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annual Review of Nutrition · 1995 · 76 citations
The Hypobetalipoproteinemias
AbstractThe fifth- and ninety-fifth-percentile concentrations of low-density lipoprotein (LDL) cholesterol in most Western populations are approximately 90 and 200 mg/dl, respectively. Persons with LDL cholesterol levels equal to or less than the fifth percentile are defined as having hypobetalipoproteinemia. Epidemiologic studies show that such individuals have lower-than-average risk for atherosclerotic cardiovascular disease but higher risk for a variety of cancers, pulmonary, and gastrointestinal diseases than persons with higher levels of cholesterol. The reasons for this are not known, nor are the causes of most cases of hypobetalipoproteinemia. However, in some well-studied kindreds the hypobetalipoproteinemia phenotype is inherited as an autosomal dominant trait. Heterozygotes in such kindreds are usually healthy and have no difficulty absorbing dietary fat. In most kindreds, the molecular variants responsible for the hypobetalipoproteinemia are unknown, but a subset of kindreds have strong genetic linkages between the low-cholesterol phenotype and truncation-producing mutations of the apolipoprotein (apo) B-100 gene. The truncations of apoB are named according to a centile nomenclature. The full-length 4536-amino acid protein is called apoB-100, and the 25 truncations identified to date have been named apoB-2 to apoB-89. The mutations introduce premature termination codons resulting from frameshift-producing base additions or deletions. The mutations produce slowed rates of secretion of the truncated apoBs relative to the apoB-100s present in the heterozygotes. In addition, the apoB-100 molecules of the heterozygotes are also secreted at rates slower than those observed in closely matched normolipidemic controls. These physiologic results account for the hypobetalipoproteinemia of these subjects. The response of the plasma lipoproteins of heterozygotes to the manipulation of various dietary components remains to be determined. Additional low-cholesterol syndromes are autosomal recessive forms of hypobetalipoproteinemia, chylomicron retention disease, and abetalipoproteinemia. The molecular causes of the first two are unknown. Abetalipoproteinemia is an autosomal recessive condition resulting from mutations of the microsomal triglyceride transfer protein. All three conditions are characterized by vanishingly small concentrations of LDL, dietary fat malabsorption, and failure to thrive in infancy.
Clinical characteristics of a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant
AbstractFamilial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder usually caused by variants in the APOB gene that frequently interfere with protein length. Clinical manifestations include malabsorption, nonalcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. We present clinical data of a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant.
Data Archiving and Networked Services (DANS) · 2022 · 0 citations · open access
Clinical characteristics of a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant
AbstractFamilial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder usually caused by variants in the APOB gene that frequently interfere with protein length. Clinical manifestations include malabsorption, nonalcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. We present clinical data of a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant.
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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