DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for microvillus inclusion 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 moduleMicrovillus inclusion 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
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 microvillus inclusion 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.
What the evidence adds up to
Microvillus inclusion disease is a rare congenital disorder causing life-threatening secretory diarrhoea from the first days of life. Two Korean infants, the first reported cases in that country, passed stools up to 200 ml/kg per day from several days after birth. Extensive infectious, immunologic, hormonal and rheumatologic testing was negative. Diagnosis was made by electron microscopy showing intracytoplasmic inclusions containing intact microvilli. The infants were treated with octreotide (4 micrograms/kg/day), cholestyramine (up to 4 g three times daily), prednisone (2 mg/kg/day) and intravenous epidermal growth factor (100 ng/kg/hr for two weeks). Only cholestyramine produced mild improvement, decreasing stool volume, and epidermal growth factor increased the number of microvilli per cell; the other treatments showed no improvement. The prognosis was described as poor.
The pathognomonic feature of microvillus inclusion disease is the presence of intracellular inclusions with discrete microvilli that express apical proteins and enzymes, suggesting the inclusions originate from the brush border. A germline Myosin Vb knockout mouse model develops numerous enterocyte inclusions and was used to study the mechanism of inclusion formation. In these mice, inclusions were positive for F-actin and for VAMP4. Inclusions attached to the brush border stained for Syndapin 2, while fully internalised inclusions were Syndapin 2 negative. Mice lacking both Myosin Vb and Syndapin 2 had very few inclusions and significantly fewer than Myosin Vb knockout mice alone; control mice had none. Live imaging of enteroids from neonatal knockout mice showed inclusion formation occurring at the apical lumen over approximately three hours, with inclusions forming omega shapes at the brush border and pinching off into the intracellular region. The authors concluded that microvillus inclusions resulting from loss of Myosin Vb are the result of endocytosis, specifically apical bulk endocytosis, and that VAMP4 and Syndapin 2 regulate the internalisation of inclusions.
No clinical trial data for any drug in microvillus inclusion disease exist beyond the single 1997 case report of four agents tested in two infants. The mouse work identifies a molecular pathway for inclusion formation but has not led to any human treatment. What is missing is any systematic clinical trial, any funding for drug development in this ultra-rare disease, and any patient stratification that might identify which infants could benefit from the modest effects seen with cholestyramine or epidermal growth factor.
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 Rheumatology · 2024 · 12 citations
Inclusion body myositis: an update
AbstractPURPOSE OF REVIEW: To review recent advances in our understanding of the epidemiology, pathophysiology, and management of inclusion body myositis (IBM). RECENT FINDINGS: Recent epidemiologic studies have highlighted the morbidity and mortality associated with IBM, including the impact of dysphagia. Multiomic analyses of IBM tissues have identified new pathogenic pathways and biomarkers for use in clinical trials. New diagnostic criteria and outcome measures have been proposed to improve clinical trial design. Ongoing clinical trials are targeting T cells and autophagy. SUMMARY: Improvements in our understanding of IBM pathogenesis are identifying new pathways and biomarkers that need validation in larger cohorts. Exercise remains the primary therapeutic modality available, and new treatment targets are needed.
Journal of Korean Medical Science · 1997 · 9 citations · open access
Microvillus inclusion disease in two Korean infants
AbstractWe report two cases of microvillus inclusion disease and these are the first cases in Korea. The two babies (one baby had a sibling who died of diarrhea in the neonatal period) had excreted their stools up to 200 ml/kg per day since several days after birth. Workup's included extensive infectious, immunologic, hormonal and rheumatologic studies, all of which were negative or normal. Diagnosis rested on the ultrastructural finding of intracytoplasmic inclusions that contained intact microvilli on electron microscopy. We tried somatostatin analogue (octreotide, 4 micrograms/kg/day), cholestyramine (up to 4g t.i.d.), steroid (prednisone, 2 mg/kg/day) and intravenous epidermal growth factor (100 ng/kg/hr for 2 weeks), but there was mild improvement with cholestyramine (decrease stool volume) and epidermal growth factor (increase the number of microvilli per cell) but no improvement was noted with the other treatments. Although it is a rare disorder and the prognosis of microvillus inclusion disease is poor, it must be considered if an infant has chronic secretory diarrhea.
Microvillus Inclusion Formation in Myosin Vb Knockout Mice Occurs Through Apical Bulk Endocytosis and Requires Syndapin 2
AbstractThe human genetic disorder, microvillus inclusion disease (MVID), causes life‐threatening diarrhea and intestinal enterocyte abnormalities. The pathognomonic intestinal characteristic of MVID is the aberrant presence of intracellular inclusions with discrete microvilli. These microvilli‐rich inclusions express a number of apical proteins and enzymes suggesting that inclusions originate from the brush border. However, whether the inclusions present in patients with MVID form via endocytosis or exocytosis remains contentious. Additionally, the mechanism of inclusion formation remains unknown. During neuronal hyper‐stimulation VAMP4 and Syndapin 1 regulate activity dependent bulk endocytosis. We postulate that in the intestine a similar, but unique, mechanism for bulk membrane internalization is occurring during the neonatal period. In the intestine, Syndapin 2 and VAMP4 are expressed on the apical membrane of enterocytes and may be involved in membrane internalization. We hypothesize that inclusion formation results from apical bulk endocytosis. Our lab has generated a germline Myosin Vb knockout (MYO5B KO) mouse to model MVID. These mice develop numerous inclusions in enterocytes making them a good model to study the mechanism of inclusion formation. MYO5B KO mice were crossed with mice expressing eGFP Lifeact, labeling F‐actin, to visualize the brush border and enable live imaging of inclusion formation in enteroids and intestinal explants. MYO5B KO mice were also bred with germline Syndapin 2 (SYN2) KO mice to generate MYO5B/Syndapin 2 double KO (MYO5B KO;SYN2 KO) mice to define the dependence of Syndapin 2 on inclusion formation. MYO5B KO mice exhibited inclusions that were F‐actin positive as well as VAMP4 positive. Additionally, inclusions attached to the brush border stained for Syndapin 2, while fully internalized inclusions were Syndapin 2 negative. Mice lacking both Myosin Vb and Syndapin 2 had very few inclusions present and significantly fewer inclusions than MYO5B KO mice. Control mice had no inclusions. 3D renderings of intestinal explants from Lifeact;MYO5B KO mice showed large inclusions that were F‐actin rich. Inclusions were either fused with the apical membrane or present as spherical inclusions below the brush border. Live imaging of enteroids derived from the duodenum of neonatal Lifeact;MYO5B KO mice showed inclusion formation occurring at the apical lumen of enteroids over a time course of approximately 3 hours. Inclusions formed omega shapes at the brush border of enteroids and pinched off into the intracellular region of enterocytes. Microvillus inclusions resulting from loss of Myosin Vb are the result of endocytosis. Apical bulk endocytosis is likely a developmental endocytotic pathway that facilitates rapid uptake and processing of nutrients during early life prior to weaning. VAMP4 and Syndapin 2 appear to regulate the internalization of inclusions. Determining the characteristics of the apical bulk endocytotic pathway in neonatal enterocytes may lead to important insights into the targeting of endocytic pathways in physiology and pathophysiology. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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