DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 1B — screening already-approved drugs against its 13-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePeroxisome biogenesis disorder 1B maps to a 13-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 peroxisome biogenesis disorder 1b 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
peroxisomal biogenesis factor 5 (PEX5) — PEX5 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 2-hydroxy-ethyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4KYO · 2.2 Å · ligand 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (BTB). Experimental structure, not a prediction.
What the evidence adds up to
The first patient with a mutation in PEX11β was identified in 2012, extending the spectrum of peroxisome biogenesis disorder (PBD) phenotypes. Peroxisomes in cells from that patient appeared enlarged and undivided, consistent with the role of PEX11 proteins in peroxisome proliferation and division. Peroxisomal fission defects are now recognised as a subgroup of PBDs. Mutations in PEX1 account for two-thirds of PBD cases. The estimated incidence of PBDs is 1 in 50,000 births in America. There is no curative therapy or long-term effective treatment available.
A 2016 dissertation described high-content screening of chemical libraries to identify small molecules that enhance peroxisome assembly and function in PBD patient cells. A novel group of compounds active at the micromolar range rescued peroxisome functions in patient cells, based on cell imaging, biochemical, and protein processing assays. The same work generated induced pluripotent stem cells (iPSCs) from PBD patient fibroblasts, differentiated them into central nervous system and hepatocyte cell lineages, and showed peroxisomal protein defects in the derived cells. HepG2 PEX1 mutant cell lines with peroxisome assembly defects were also generated.
A Pex1-p.G844D mouse was characterised as the first mouse model with hypomorphic PEX alleles, intended to better model PBD patients with milder clinical features. Gene expression profiling of the murine retina and recovery of peroxisomal protein import by adeno-associated virus (AAV)-mediated gene expression suggested the mice could serve as a model for investigating retinal gene therapy. The iPSC, iPSC-derived cells, murine model skin fibroblasts, and HepG2 cells carrying common PEX1 mutations were proposed for future chemical library screening.
What is still missing is any clinical trial of the identified small molecules in patients, any demonstration that the compounds improve clinical outcomes rather than cellular markers, and any validated patient stratification strategy for the genetically heterogeneous PBD population. Funding for clinical translation and for moving from cell and mouse models to human testing remains absent.
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 Medical Genetics · 2012 · 34 citations
First PEX11β patient extends spectrum of peroxisomal biogenesis disorder phenotypes: Table 1
AbstractAmong the human PEX genes associated with peroxisome biogenesis disorders, only the PEX11 family genes had not previously been associated with human disease. A new study identifies the first patient with a mutation in PEX11β. The patient presents with symptoms atypical for peroxisome biogenesis disorders. Peroxisomes in cells derived from this patient appear enlarged and undivided, complying with the role of PEX11 proteins in peroxisome proliferation and division. These new findings widen the spectrum of clinical and cellular phenotypes of diseases associated with defective peroxisome formation.
Topics in Magnetic Resonance Imaging · 2018 · 15 citations
Clinical and Neuroimaging Spectrum of Peroxisomal Disorders
AbstractPeroxisomes play vital roles in a broad spectrum of cellular metabolic pathways. Defects in genes encoding peroxisomal proteins can result in a wide array of disorders, depending upon the metabolic pathways affected. These disorders can be broadly classified into 2 main groups; peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies. Peroxisomal enzyme deficiencies are result of dysfunction of a specific metabolic pathway, while PBDs are due to generalized peroxisomal dysfunction. Mutations in PEX1 gene are the most common cause of PBDs, accounting for two-thirds of cases. Peroxisomal fission defects is a recently recognized entity, included under the subgroup of PBDs. The aim of this article is to provide a comprehensive review on the clinical and neuroimaging spectrum of peroxisomal disorders.
University of Southern California Digital Library · 2016 · 0 citations · open access
Development of targeted therapies for peroxisome biogenesis disorders
AbstractPeroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous rare metabolic diseases caused by defects in peroxins, proteins encoded by PEX genes that function in peroxisome biogenesis. PBDs display an autosomal recessive mode of transmission with an estimated incidence of 1 in 50,000 births in America. Although the genetic basis of PBDs is well understood, there is currently no curative therapy or long-term effective treatment available. ? In this dissertation, I described the identification and characterization of small molecules that enhance peroxisome assembly and function in PBD patient cells through high-content screening (HCS) of chemical libraries. Our therapeutic hypothesis is that the rescue of peroxisome assembly and functions will be of therapeutic benefit to individuals with peroxisome biogenesis disorders. We uncovered a novel group of compounds active at the micromolar range that rescued peroxisome functions in patient cells based on cell imaging, biochemical, and protein processing assays. Overall, the novel bioactive small molecules we identified could provide tools for investigating peroxisome biogenesis and novel leads for the development of targeted small molecule therapies, and the new cellular and animal models can be the next generation screening tools to discover and characterize more active compounds. ? In addition, I describe the development of new model systems of PBDs, including induced pluripotent stem cells (iPSCs), HepG2 cells and mice. We generated iPSCs from primary skin fibroblasts of PBD patients and differentiated them into central nervous system (CNS) and hepatocyte cell lineages and showed peroxisomal protein defects of the derived cells. We also generated and characterized HepG2 PEX1 mutant cell lines with peroxisome assembly defects. Finally, I also participated in the characterization of the Pex1-p.G844D mouse which is the first mouse model with hypomorphic PEX alleles and thus better disease model for PBD patients with milder clinical features. Gene expression profiling of the murine retina and the recovery of peroxisomal protein import by adeno-associated virus (AAV)-mediated gene expression suggested that the mice can serve as a powerful model system for investigating retinal gene therapy. Overall, These iPSC, iPSC-derived cells, murine model skin fibroblast and HepG2 cells carrying common PEX1 mutations can have future applications for chemical library screening for candidate drugs that directly address the cell type specificity of disease and the nature of the mutations found in the patient population.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
