DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Gaucher disease — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGaucher disease maps to a 3-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 gaucher 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
sphingomyelin phosphodiesterase 1 (SMPD1) — SMPD1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5I81 · 2.25 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Gaucher disease is an autosomal recessive disorder caused by congenital deficiency of lysosomal glucocerebrosidase, classified into three types. Over 200 mutations in the GBA gene have been identified worldwide. In a 2004 expression study of 13 mutant alleles in Sf9 cells, five alleles produced negligible residual enzyme activity: c.662C>T (p.P182L), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1289C>T (p.P391L), and c.1292A>T (p.N392I). The alleles c.1226A>G (p.N370S), c.1322T>C (p.I402T), c.1342G>C (p.D409H), c.1448T>C (p.L444P), and the double mutant [p.L444P; p.E326K] produced enzymes with 6 to 14% of wild-type activity. Three alleles showed higher activity: c.680A>G (p.N188S) at 66.6%, c.1093G>A (p.E326K) at 42.7%, and the double mutant [p.N188S; p.E326K] at 23.2%. The p.E326K change was never found alone in a Gaucher disease-causing allele, but when present in double mutants it decreased activity compared to the other mutation alone, suggesting it is a modifier variant rather than a neutral polymorphism.
A retrospective study of 20 untreated type I Gaucher disease patients in the Netherlands found that clinical manifestations were progressive in the majority of patients, both children and adults, in contrast to studies among Jewish patients. The authors emphasised the need for regular follow-up to enable timely initiation of enzyme therapy. A 2012 review noted that the clinical presentation is very variable and little has been understood of the determinants of heterogeneity. Registry data have furthered understanding of individual risk factors for bone complications including fractures and osteonecrosis, and for reduced or delayed response to enzyme replacement therapy. A genome-wide association study identified a previously unsuspected gene as a potential modifier of severity.
A 2015 review stated that in addition to enzyme replacement therapy, substrate reduction therapy, chemical chaperon therapy, and hematopoietic stem cell transplantation are considered for treatment. A 2022 systematic review and meta-analyses of longitudinal studies on drug treatments for Gaucher disease was published, but the abstract provided does not give its results.
What is still missing is a clear understanding of the biological determinants of disease heterogeneity, validated biomarkers for assessing disease burden and treatment response in routine practice, and prospective trials that stratify patients by genotype and modifier variants to predict which individuals will progress and who will benefit most from each treatment modality.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2004 · 90 citations · open access
Functional analysis of 13<i>GBA</i>mutant alleles identified in Gaucher disease patients: Pathogenic changes and “modifier” polymorphisms
AbstractGaucher disease, the most prevalent sphingolipidosis, is caused by the deficient activity of acid beta-glucosidase, mainly due to mutations in the GBA gene. Over 200 mutations have been identified worldwide, more than 25 of which were in Spanish patients. In order to demonstrate causality for Gaucher disease, some of them: c.662C>T (p.P182L), c.680A>G (p.N188S), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1093G>A (p.E326K), c.1289C>T (p.P391L), c.1292A>T (p.N392I), c.1322T>C (p.I402T), and the double mutants [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), were expressed in Sf9 cells using a baculovirus expression system. Other well-established Gaucher disease mutations, namely c.1226A>G (p.N370S), c.1342G>C (p.D409H), and c.1448T>C (p.L444P), were also expressed for comparison. The levels of residual acid beta-glucosidase activity of the mutant enzymes produced by the cDNAs carrying alleles c.662C>T (p.P182L), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1289C>T (p.P391L), and c.1292A>T (p.N392I) were negligible. The c.1226A>G (p.N370S), c.1322T>C (p.I402T), c.1342G>C (p.D409H), c.1448T>C (p.L444P), and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]) alleles produced enzymes with levels ranging from 6 to 14% of the wild-type. The three remaining alleles, c.680A>G (p.N188S), c.1093G>A (p.E326K), and [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]), showed higher activity (66.6, 42.7, and 23.2%, respectively). Expression studies revealed that the c.1093G>A (p.E326K) change, which was never found alone in a Gaucher disease-causing allele, when found in a double mutant such as [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), decreases activity compared to the activity found for the other mutation alone. These results suggest that c.1093G>A (p.E326K) should be considered a "modifier variant" rather than a neutral polymorphism, as previously considered. Mutation c.680A>G (p.N188S), which produces a mutant enzyme with the highest level of activity, is probably a very mild mutation or another "modifier variant."
Journal of Inherited Metabolic Disease · 2000 · 45 citations
The natural course of Gaucher disease in The Netherlands: Implications for monitoring of disease manifestations
AbstractThis retrospective study in 20 untreated type I Gaucher disease patients shows that in Dutch patients clinical manifestations of Gaucher disease type I are progressive in the majority of patients, children as well as adults. This is in contrast with studies among Jewish patients. Our results emphasize the need for a regular follow-up to enable timely initiation of enzyme therapy.
Current Opinion in Hematology · 2012 · 17 citations
Haematological manifestations and complications of Gaucher disease
AbstractPURPOSE OF REVIEW: Gaucher disease is a rare inherited disorder of sphingolipid metabolism resulting in the accumulation of glucocerebroside substrate in cells throughout the reticuloendothelial system and clinical manifestations including cytopenias, organomegaly and bone disease. The clinical presentation is very variable and little has been understood of the determinants of heterogeneity or biological features that influence disease severity. RECENT FINDINGS: This review explores the haematological features of Gaucher disease in the context of new insights into the underlying cellular physiopathlogy. Careful examination of registry data has furthered understanding of individual risk factors for bone complications including fractures and osteonecrosis and for reduced or delayed response to enzyme replacement therapy. Analysis of substrates and their derivatives have added to possible biomarkers for assessment of disease burden and response to treatment and strikingly, in view of its rarity a genome-wide association study has identified a hitherto unsuspected gene as a potential modifier of severity. SUMMARY: Improved understanding of biological and clinical risk factors for severe manifestations of Gaucher disease will allow rational assessment of patients and suggests potential nonsubstrate directed adjuvant strategies to consider in the management of this condition.
AbstractGaucher disease is an autosomal recessive disorder caused by congenital deficiency of lysosomal glucocerebrosidase. Gaucher disease is classified into three types. In addition to enzyme replacement therapy, substrate reduction therapy, chemical chaperon therapy, and hematopoietic stem cell transplantation therapy are considered for the effective treatment of Gaucher disease.
Sage Journals Data · 2022 · 0 citations · open access
sj-rar-1-aop-10.1177_10600280221108443 – Supplemental material for A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease
AbstractSupplemental material, sj-rar-1-aop-10.1177_10600280221108443 for A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease by Letícia Paula Leonart, Mariana M. Fachi, Beatriz Böger, Mariana Ribeiro da Silva, Renata Szpak, Natália Fracaro Lombardi, Maria Lucia Alves Pedroso and Roberto Pontarolo in Annals of Pharmacotherapy
sj-rar-1-aop-10.1177_10600280221108443 – Supplemental material for A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease
AbstractSupplemental material, sj-rar-1-aop-10.1177_10600280221108443 for A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease by Letícia Paula Leonart, Mariana M. Fachi, Beatriz Böger, Mariana Ribeiro da Silva, Renata Szpak, Natália Fracaro Lombardi, Maria Lucia Alves Pedroso and Roberto Pontarolo in Annals of Pharmacotherapy
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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