DeCure for Congenital sucrase-isomaltase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital sucrase-isomaltase deficiency — 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 moduleCongenital sucrase-isomaltase deficiency 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 congenital sucrase-isomaltase 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
sucrase-isomaltase (SI) — SI 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 1s,2r,3r,4sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3LPP · 2.15 Å · ligand (1S,2R,3R,4S)-1-{(1S)-2-[(2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrothiophenium-1-yl]-1-hydroxyethyl}-2,3,4,5-tetrahydroxypentyl sulfate (KTL). Experimental structure, not a prediction.
What the evidence adds up to
Congenital sucrase-isomaltase deficiency results from mutations in the sucrase-isomaltase gene. A 1988 study of eight cases identified at least three cellular phenotypes: one where the enzyme precursor accumulated as a membrane-associated high-mannose form, probably in the endoplasmic reticulum; one where transport appeared blocked in the Golgi apparatus; and one where catalytically altered enzyme reached the cell surface. All patients expressed electrophoretically normal or near-normal high-mannose sucrase-isomaltase, suggesting that different, probably small, mutations cause the deficiency.
A 2021 cross-sectional interview study of 43 US patients (8 adults, 35 children/adolescents) who had been prescribed and taking sacrosidase for at least three consecutive months reported that after diagnosis and treatment with sacrosidase, participants described considerable improvement in symptoms and health-related quality of life, yet symptoms persisted that continued to affect daily life. The authors noted this was the first study of its kind in CSID and called for additional qualitative and quantitative research.
A 2024 pedigree study of 109 family members of an index case with a homozygous c.317G>A (p.C106Y) mutation found 27 heterozygous carriers (24.7%). Among these, 12 (44.4%) were symptomatic; the most common complaints were abdominal pain (37%), gas irritability (33.3%), bloating (22.2%), and foul-smelling stools (18.5%). Compared with family members without the mutation, heterozygous carriers had statistically significantly higher rates of gas irritability, foul-smelling stool, two or more gastrointestinal symptoms, postprandial complaints, and food allergy. Sacrosidase enzyme replacement was given to seven patients whose symptoms did not improve with dietary elimination, and clinical response was obtained. The authors concluded that CSID can be symptomatic in heterozygous individuals despite its autosomal recessive inheritance.
Another 2024 study using whole exome sequencing in 300 patients referred to a medical genetics unit found SI gene mutations in 25 (8.3%): one compound heterozygous and 24 heterozygous. Nine of the 25 (36%) were symptomatic. The authors noted that their cohort consisted of patients with suspected genetic diseases rather than healthy individuals, and that large-scale population-based studies are needed. What remains missing is a clear genotype-phenotype map that explains why some heterozygotes are symptomatic while others are not, prospective data on the natural history of untreated CSID, and a randomised controlled trial of sacrosidase that measures objective outcomes rather than relying solely on patient-reported improvement.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Clinical Investigation · 1988 · 118 citations · open access
Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme.
AbstractEight cases of congenital sucrase-isomaltase deficiency were studied at the subcellular and protein level with monoclonal antibodies against sucrase-isomaltase. At least three phenotypes were revealed: one in which sucrase-isomaltase protein accumulated intracellularly probably in the endoplasmic reticulum, as a membrane-associated high-mannose precursor, one in which the intracellular transport of the enzyme was apparently blocked in the Golgi apparatus, and one in which catalytically altered enzyme was transported to the cell surface. All patients expressed electrophoretically normal or near normal high-mannose sucrase-isomaltase. The results suggest that different, probably small, mutations in the sucrase-isomaltase gene lead to the synthesis of transport-incompetent or functionally altered enzyme which results in congenital sucrose intolerance.
Quality of Life Research · 2021 · 31 citations · open access
The patient journey to diagnosis and treatment of congenital sucrase-isomaltase deficiency
AbstractPURPOSE: Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic disorder characterized by a deficiency of the sucrase-isomaltase (SI) enzyme complex within the brush border membrane of the small intestine. Mutations in the SI gene result in abnormal synthesis and/or incorrect transport of the SI enzyme. Patients with CSID generally have reduced sucrase activity, but levels of isomaltase activity range from absent to almost normal. This study sought to better understand the experience of patients with CSID prior to, during, and after their diagnosis and its subsequent treatment with sacrosidase. METHODS: This was a cross-sectional interview study conducted in conjunction with a longitudinal, observational study of US patients prescribed and taking sacrosidase for at least three consecutive months as treatment for CSID. The observational study included both children and adults. RESULTS: This qualitative interview study explored the experiences of 43 adult and pediatric patients (n = 8 adults and n = 35 children/adolescents) with CSID pre-, during, and post-diagnosis. Findings suggest that a CSID diagnosis is particularly problematic given the disparate range of more commonly understood gastrointestinal (GI) disorders. After diagnosis and treatment with sacrosidase, participants reported considerable improvement in symptoms and health-related quality of life (HRQL), yet symptoms persist that continue to affect daily life, indicating areas of potential unmet need. CONCLUSION: Educating clinicians about CSID may help improve the overall diagnosis experience. As this research is the first of its kind in CSID, additional research, qualitative and quantitative, will be important to furthering the understanding of HRQL impact and unmet need experienced by this population and identifying ways to best meet those needs.
The Turkish Journal of Gastroenterology · 2024 · 2 citations · open access
Congenital Sucrase–Isomaltase Deficiency: Same Mutation with Different Clinical Presentations
AbstractBACKGROUND/AIMS: Congenital sucrase-isomaltase deficiency is an autosomal recessive inherited disaccharidase deficiency characterized by chronic osmotic diarrhea. In this study, the genotype-phenotype relationships of close relatives of an index case with congenital sucrase-isomaltase deficiency were investigated. MATERIALS AND METHODS: A 23-month-old female patient with a sucrase-isomaltase gene c.317G>A (p.C106Y) homozygous mutation was diagnosed as an index case and her pedigree analysis was performed subsequently. The family members with and without sucrase- isomaltase gene mutations were compared in terms of clinical symptoms. RESULTS: The study included 109 cases [mean age ± SD: 22.6 ± 17.2 years (0.1-75 years), 61 males (56%)] of 130 family members of the index case. Sucrase-isomaltase gene c.317G>A (p.C106Y) heterozygous mutation was detected in 27 cases (24.7%); 14 (51.9%) were male and had a mean age of 23.2 ± 18.3 years. The most common complaints of 12 (44.4%) symptomatic patients with mutations were abdominal pain (37%), gas irritability (33.3%), bloating (22.2%), and foul-smelling stools (18.5%). Compared with the cases without mutation, a statistically significant difference was observed in the incidence of gas irritability, foul-smelling stool, ≥2 gastrointestinal symptoms, postprandial complaints, and food allergy (P = .005, P = .047, P = .049, P = .017, P = .021, respectively). Sacrosidase enzyme replacement was applied to 7 patients whose symptoms did not improve with dietary elimination. Clinical response was obtained after enzyme treatment. CONCLUSION: Despite its autosomal recessive inheritance, congenital sucrase-isomaltase deficiency can also be symptomatic in heterozygous individuals. Further studies are required to clarify the genotype-phenotype relationship and management of the disease.
The Journal of Pediatric Research · 2024 · 1 citations · open access
Frequency of Congenital Sucrase-Isomaltase Deficiency by Whole Exome Sequencing: Is It Really Rare?
AbstractAim: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive disease with a mutation in the sucrase-isomaltase (SI) gene and disaccharide maldigestion. With limited data, the estimated incidence of this disease is 57.59/10⁶ births and its heterozygosity rate is 1/132. We aimed to evaluate cases who underwent whole exome sequencing (WES) analysis in the medical genetics unit with regards to the frequency and clinic of CSID. Materials and Methods: The patients’ files who underwent WES between 2018-2023 were evaluated retrospectively. The demographic characteristics, complaints, physical examination, and laboratory findings of those patients with SI gene mutations were recorded. Cases with mutations were recontacted and symptom questioning was performed. Results: Mutations were detected in 25 (8.3%) of 300 patients who underwent WES analysis. One case had a compound heterozygous mutation, while 24 cases were heterozygous. The mean age was 22.4±17.6 years (1.8-52 years) and 16 (64%) were females. Nine of the cases (36%) were symptomatic. Conclusion: Data on the frequency of CSID are insufficient and variable in the literature. The SI heterozygosity rate in our study was higher than some studies. There were similar rates when compared to the study conducted on symptomatic pediatric patients in our country. Although the data of our study includes a heterogeneous group to evaluate the frequency of CSID, it consists of a group with suspected genetic diseases rather than healthy individuals. Therefore, large-scale population-based studies are needed.
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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