DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for chylomicron retention disease — 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 moduleChylomicron retention disease 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
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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 chylomicron retention disease 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
secretion associated Ras related GTPase 1B (SAR1B) — SAR1B 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 gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8E0A · 1.797 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
Chylomicron retention disease is an autosomal recessive disorder caused by mutations in the SAR1B gene, which encodes the SAR1B GTPase protein. These mutations disable the formation of coat protein complex II, blocking the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. The result is a total absence of chylomicrons and apolipoprotein B-48 in the blood after a fat meal, accompanied by deficiency of liposoluble vitamins and essential fatty acids. One 2018 case report identified a previously undescribed homozygous mutation, c.83_84delTG(p.Leu28Argfs*7), in the SAR1B gene. Another 2018 report described a two-year-old girl with a novel deletion in SAR1B whose treatment was delayed while awaiting genetic confirmation unavailable in her country.
The clinical picture includes failure to thrive, chronic diarrhoea, steatorrhea, abdominal distension, and vomiting in early childhood. Later complications can include ataxic neuropathy and visual impairment. Hypocholesterolemia in these patients may reflect decreased HDL cholesterol, possibly due to limited intestinal HDL production from reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I. Experimental studies suggest the paralog SAR1A can compensate for the lack of SAR1B. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may help explain how large chylomicrons are exported despite exceeding coat protein complex II size.
Management described in case reports consists of a low-fat diet supplemented with medium-chain fatty acids and fat-soluble vitamins. In the two-year-old girl, this regimen produced rapid recovery from severe failure to thrive. The 2018 case report of the new mutation states that adequate management can reverse malnutrition and avoid irreversible complications. A 1948 study of chylomicron counts in patients with sprue found that low chylomicron curves returned to normal after two to three weeks of parenteral liver therapy, but this finding predates the molecular definition of chylomicron retention disease and its distinction from other fat malabsorption disorders.
What remains missing are prospective trials of any specific dietary or pharmacological intervention in genetically confirmed chylomicron retention disease patients, systematic data on long-term outcomes with current management, and any evidence that the paralog SAR1A compensation observed experimentally can be harnessed therapeutically. The disease is very rare, with prevalence below one per million, which makes patient stratification and trial design difficult and limits funding for dedicated research.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Lipidology · 1995 · 67 citations
Chylomicron remnants: hepatic receptors and metabolism
AbstractRecent studies support a sequential model for hepatic processing and catabolism of chylomicron remnants. Removal of chylomicron remnants by the liver involves interaction with several macromolecules on the cell surface, including the LDL receptor and heparan-sulfate-bound hepatic lipase and apolipoprotein E. Endocytosis of chylomicron remnants into hepatocytes is mediated by apolipoprotein E and normally occurs through the LDL receptor. Interaction of chylomicron remnants with the LDL receptor-related protein, or another endocytic receptor with similar properties, occurs slowly, requiring modification of surface-bound chylomicron remnants, and serves as a backup mechanism that is utilized primarily when LDL receptors are deficient or down-regulated.
Current Opinion in Lipidology · 2019 · 55 citations
Chylomicron retention disease: genetics, biochemistry, and clinical spectrum
AbstractPURPOSE OF REVIEW: Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B or SARA2 gene encoding for intracellular SAR1B GTPase protein. The aim of this review is first to provide an update of the recent biochemical, genetic and clinical findings, and second to discuss novel mechanisms related to hallmark symptoms. RECENT FINDINGS: CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. Consequently, there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may explain the intriguing export of large chylomicron, exceeding coat protein complex II size. Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein. In experimental studies, the paralog SAR1A compensates for the lack of the SAR1B GTPase protein. SUMMARY: Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions, and to early define molecular aberrations, accelerate treatment, and prevent complications.
Bioscience Reports · 2012 · 42 citations · open access
<i>Trans</i>-Golgi proteins participate in the control of lipid droplet and chylomicron formation
AbstractLDs (lipid droplets) carrying TAG (triacylglycerol) and cholesteryl esters are emerging as dynamic cellular organelles that are generated in nearly every cell. They play a key role in lipid and membrane homoeostasis. Abnormal LD dynamics are associated with the pathophysiology of many metabolic diseases, such as obesity, diabetes, atherosclerosis, fatty liver and even cancer. Chylomicrons, stable droplets also consisting of TAG and cholesterol are generated in the intestinal epithelium to transport exogenous (dietary) lipids after meals from the small intestine to tissues for degradation. Defective chylomicron formation is responsible for inherited lipoprotein deficiencies, including abetalipoproteinaemia, hypobetalipoproteinaemia and chylomicron retention disease. These are disorders sharing characteristics such as fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. Thus understanding the molecular mechanisms governing the dynamics of LDs and chylomicrons, namely, their biogenesis, growth, maintenance and degradation, will not only clarify their molecular role, but might also provide additional indications to treatment of metabolic diseases. In this review, we highlight the role of two small GTPases [ARFRP1 (ADP-ribosylation factor related protein 1) and ARL1 (ADP-ribosylation factor-like 1)] and their downstream targets acting on the trans-Golgi (Golgins and Rab proteins) on LD and chylomicron formation.
Chylomicron Retention Disease: a Description of a New Mutation in a Very Rare Disease
AbstractChylomicron retention disease, also known as Anderson's disease, is a rare hereditary hypocholesterolemic disorder, recessive inherited, characterized by nonspecific symptoms as abdominal distension, steatorrhea, and vomiting associated with failure to thrive. We describe a patient with failure to thrive, chronic diarrhea and steatorrhea who the diagnosis of chylomicron retention disease was established after several months of disease progression. The genetic study confirmed a homozygosity mutation in SAR1B gene, identifying a mutation never previous described [c.83_84delTG(p.Leu28Argfs*7)]. With this case report the authors aim to highlight for this very rare cause of failure to thrive and for the importance of an attempting diagnosis, in order to start adequate management with low fat diet supplemented with fat-soluble vitamins, reverting the state of malnutrition and avoiding possible irreversible and desvantating complications.
Transactions of the Royal Society of Tropical Medicine and Hygiene · 1948 · 6 citations
The chylomicron count in normal subjects and patients with sprue
AbstractChylomicron curves were done on eleven normal subjects (eighteen curves) and on twenty-eight patients with sprue (eighty-seven curves). With a meal containing 18 grammes of fat, the peak count in normals ranged between 100 and 270 particles per standard field. The chylomicron curve in normals increased and diminished when more or less fat was given, suggesting that chylomicrons do represent at least one form of absorbed fat. On the other hand, low curves were produced in normals by giving calcium lactate with the meal; in fat balance experiments, calcium lactate did not produce steatorrhoea, so the fraction of ingested fat involved in producing a normal chylomicron count must be quite small. Moreover, in cases of sprue little relation was found between the height of the curve and the degree of steatorrhoea; and when “flat” chylomicron curves returned to normal with clinical improvement, there was no corresponding diminution in the steatorrhoea. Concurrent chylomicron curves and serum lipide curves in sprue patients showed that chylomicrons represent a variable fraction of the absorbed neutral fat in the serum. In untreated sprue low curves were found in about half of the patients examined. After 2 or 3 weeks of parenteral liver therapy, patients whose curves had been low gave normal curves. It is concluded that a small proportion of the total fat is absorbed without splitting as finely emulsified neutral fat. While all patients with sprue have a defective absorption of split fat, only some show impaired neutral fat absorption as judged by the chylomicron count. Failure to absorb neutral fat is more common in the severe cases and responds to liver therapy.
Indian Journal of Child Health · 2018 · 2 citations · open access
Chylomicron retention disease in a 2-year-old girl with a novel deletion in the SAR1b gene: A case report and literature review
AbstractChylomicron retention disease (CMRD) is a rare disorder of lipid absorption, and its prevalence is <1/million. It is an autosomal recessive disorder with a genetic mutation in the SAR1B gene. We report a case of a girl who had the typical symptoms in the early infancy, in whom CMRD was strongly suspected clinically and due to the endoscopy findings. Unfortunately, the treatment was delayed, waiting for genetic confirmation, which was not available in her country. When we first saw the patient at the age of 2 years, she had severe failure to thrive. She recovered very fast with a trial of a fat-restricted diet and medium chain fatty acid supplementation. The working diagnosis of CMRD was later confirmed genetically. We conclude that a therapeutic trial is essential in this type of disease once the diagnosis is suspected to avoid further damage to the patient. This applies especially to resource-restricted environments.
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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