DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 2B — screening already-approved drugs against its 8-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 2B maps to a 8-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 2b 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
Peroxisome biogenesis disorder 2B is one of the peroxisome biogenesis disorders (PBDs) caused by defects in PEX genes. In PEX5-deficient cell lines from 11 patients, mutation analysis revealed 11 different mutations, eight of which were novel. Six of those cell lines showed a defect in both PTS1 and PTS2 protein import, while four showed a defect only in PTS1 import. The location of the mutation within the PEX5 amino acid sequence correlated with the observed import defect.
There is currently no curative therapy or long-term effective treatment available for peroxisomal disorders. High-content screening of chemical libraries identified small molecules active at the micromolar range that rescued peroxisome functions in patient cells based on cell imaging, biochemical, and protein processing assays. These compounds are described as novel leads for developing targeted small molecule therapies, but no specific drug names, response rates, or survival data are reported in these abstracts.
Induced pluripotent stem cells (iPSCs) have been generated from skin fibroblasts of PBD patients and differentiated into central nervous system cell lineages and hepatocyte cell lineages, showing peroxisomal protein defects in the derived cells. A Pex1-p.G844D mouse model with hypomorphic PEX alleles has been characterised, and gene expression profiling of the murine retina along with recovery of peroxisomal protein import by AAV-mediated gene expression suggested the mice could serve as a model for retinal gene therapy.
What is still missing is any clinical trial data in patients, any evidence that the small molecules identified in cell-based screens produce benefit in living animals or humans, and any validated patient stratification strategy that would match a specific PEX mutation to a specific therapy. The existing models have not yet been used for large-scale drug testing in a way that has produced a treatment.
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 · 2008 · 22 citations
Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines
AbstractProteins destined for the peroxisomal matrix are targeted by virtue of a peroxisomal targeting sequence type 1 (PTS1) or type 2 (PTS2). In humans, targeting of either class of proteins relies on a cytosolic receptor protein encoded by the PEX5 gene. Alternative splicing of PEX5 results in two protein variants, PEX5S and PEX5L. PEX5S is exclusively involved in PTS1 protein import, whereas PEX5L mediates the import of both PTS1 and PTS2 proteins. Genetic complementation testing with over 500 different fibroblast cell lines from patients diagnosed with a peroxisome biogenesis disorder (PBD) identified 11 cell lines with a defect in PEX5. The aim of this study was to characterize these cell lines at a biochemical and genetic level. To this end, the cultured fibroblasts were analyzed for very long chain fatty acid (VLCFA) concentrations, peroxisomal beta-and alpha-oxidation, dihydroxyacetone-phosphate acyltransferase (DHAPAT) activity, peroxisomal thiolase, and catalase immunofluorescence. Mutation analysis of the PEX5 gene revealed 11 different mutations, eight of which are novel. PTS1- and PTS2-protein import capacity was assessed by transfection of the cells with green fluorescent protein (GFP) tagged with either PTS1 or PTS2. Six cell lines showed a defect in both PTS1 and PTS2 protein import, whereas four cell lines only showed a defect in PTS1 protein import. The location of the different mutations within the PEX5 amino acid sequence correlates rather well with the peroxisomal protein import defect observed in the cell lines.
AbstractABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Vanessa Gomez is first author on ‘ Distinguishing PEX gene variant severity for mild, severe, and atypical peroxisome biogenesis disorders’, published in DMM. Vanessa is a Research Assistant in the lab of Michael F. Wangler at Baylor College of Medicine, Houston, TX, investigating rare human disease phenotypes to advance our understanding of biological principles that govern health and disease.
University of Southern California Digital Library · 2012 · 0 citations · open access
IPS and CNS cell models of peroxisomal disorders
AbstractPeroxisomal disorders are a group of genetically heterogeneous metabolic diseases caused by defects in peroxins, proteins encoded by PEX genes that function in peroxisome biogenesis, or in a single peroxisomal protein that has a more targeted effect on specific peroxisome functions. In general, peroxisome disorders can affect almost every organ system, with especially devastating effects on the nervous, hepatic, and adrenocortical systems. ? Currently, there is no curative therapy or long-term effective treatment available for peroxisomal disorders. Ongoing pathomechanism studies, diagnostics, and drug testing are mainly established on patient-derived primary fibroblasts and Pex gene knockout mouse models, which do not represent the exact human mutations and most clinical aspects of the human disease. ? In this thesis, I describe a new model system which we established for studying the pathology of peroxisomal disorders and testing new therapeutic agents. We generated induced pluripotent stem cells (iPSCs) from primary skin fibroblasts of multiple healthy controls and patients with peroxisomal biogenesis disorders (PBD), caused by genetic defects in PEX genes, or the childhood cerebral form of X-linked adrenoleukodystrophy (CCALD), caused by genetic defects in the ABCD1 gene that encodes a peroxisome membrane protein involved in very long chain fatty acid (VLCFA) metabolism. Candidate iPSCs were subject to global expression, DNA methylation, and genotyping analysis and tested for pluripotency through in vitro embryoid body differentiation and in vivo teratoma formation. We characterized the gene expression and biochemical profiles of these patient-specific iPSCs and further differentiated these iPSCs into pathologically related central nervous system cell (CNSC) lineages, including neural progenitors, motor neurons, and oligodendrocytes. ? Our molecular characterization of iPSCs and CNSCs provided a novel perspective into disease mechanisms that supports leading hypotheses regarding disease pathogenesis including the pivotal roles of neuroinflammation, lipid metabolism, and aberrant mitochondrial function. Our novel resources also provide a first step required for the development and interpretation of patient-specific model systems that investigate non-cell autonomous processes relevant to the etiology of peroxisomal disorders. These iPSC and CNS cell resources could also have applications for high content screening (HCS) of chemical libraries for candidate drugs that directly address the cell type specificity of disease and the nature of the mutations found in the patient population.
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.
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