DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital lactase 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 lactase 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 lactase 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.
What the evidence adds up to
Congenital lactase deficiency is a rare severe gastrointestinal disorder of newborns, enriched in the Finnish population, caused by autosomal recessive mutations in the lactase (LCT) gene. The mutations result in low levels of lactase-phlorizin hydrolase (LPH) activity through nonsense-mediated LCT mRNA decay or misfolded proteins that cannot exit the endoplasmic reticulum and are degraded. In a Japanese infant with CLD, two heterozygous mutations, c.4419C>G (p.Y1473X) and c.5387delA (p.D1796fs), produced mutant proteins with no detectable enzymatic activity, despite the presence of active sites in the polypeptide backbone. Wild type LPH retained complete enzymatic activity and intracellular transport competence in the presence of these pathogenic mutants, indicating that heterozygote carriers presumably do not show symptoms.
The disorder presents a few days after birth with watery diarrhea, meteorism, and malnutrition. The only treatment described in these abstracts is lactose avoidance. No drug therapy, repurposed or otherwise, is mentioned in any of the three abstracts. The molecular mechanisms are well characterised: adult-type hypolactasia (present in over half the human population) is mediated by distal enhancer polymorphisms regulating developmental LCT transcript levels, while CLD is caused by coding-region mutations that destroy enzyme function entirely.
What is still missing is any clinical trial of a pharmacological intervention for congenital lactase deficiency. There is no evidence of enzyme replacement therapy, gene therapy, or chaperone-based approaches being tested in patients. The abstracts provide no data on survival rates, response rates, or sample sizes beyond single case reports. The rarity of the condition means that any future trial would require international collaboration and funding for patient stratification by specific LCT mutation type.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Medicine · 2009 · 76 citations · open access
Molecular genetics of human lactase deficiencies
AbstractLactase non-persistence (adult-type hypolactasia) is present in more than half of the human population and is caused by the down-regulation of lactase enzyme activity during childhood. Congenital lactase deficiency (CLD) is a rare severe gastrointestinal disorder of new-borns enriched in the Finnish population. Both lactase deficiencies are autosomal recessive traits and characterized by diminished expression of lactase activity in the intestine. Genetic variants underlying both forms have been identified. Here we review the current understanding of the molecular defects of human lactase deficiencies and their phenotype-genotype correlation, the implications on clinical practice, and the understanding of their function and role in human evolution.
Molecular Differentiation of Congenital Lactase Deficiency from Adult-Type Hypolactasia
AbstractA limited fraction of the human adult population retains intestinal lactase-phlorizin hydrolase (LPH) activity during adulthood, and this is called the lactase persistence phenotype. However, 95% of all adults have adult-type hypolactasia (ATH) and have difficulty digesting milk sugar. Rarely, some infants are born with an inability to digest lactase (congenital lactase deficiency or CLD) due to low levels of LPH activity, which results in severe clinical consequences if not properly diagnosed and treated by lactose avoidance. Recently, it has been shown that both recessive LPH deficiencies, CLD and ATH, are related to DNA variants affecting the lactase (LCT) gene, but they are mediated through very different molecular mechanisms. The LCT mutations resulting in childhood CLD lead to low LPH activity through nonsense-mediated LCT mRNA decay, whereas the critical nucleotide variants for the ATH phenotype represent distal enhancer polymorphisms, which regulate developmentally LCT transcript levels in intestinal cells.
Compound heterozygous mutations elicit congenital lactase deficiency in a Japanese infant
AbstractCongenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase‐phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C>G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD. Here, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. We show that both mutant proteins are mannose‐rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH‐D1796fs and LPH‐Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD. Our study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance.
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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