DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder type 3B — screening already-approved drugs against its 6-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 type 3B maps to a 6-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 type 3b 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
A single patient with a mutation in PEX11β has been identified, the first human case linking the PEX11 family to peroxisome biogenesis disorders. That patient’s peroxisomes were enlarged and undivided, consistent with the known role of PEX11 proteins in peroxisome proliferation and division, and the clinical presentation was described as atypical for peroxisome biogenesis disorders. No other PEX11β patients have been reported, and no treatment data are available for this specific genotype.
In PEX5-deficient cell lines, mutation analysis of 11 patient fibroblast lines found 11 different mutations, eight of them novel. Six lines had defects in both PTS1 and PTS2 protein import; four lines had defects only in PTS1 import. The location of the mutation within the PEX5 amino acid sequence correlated with the import defect observed. These cell lines were characterised by measuring very long chain fatty acid concentrations, peroxisomal beta- and alpha-oxidation, DHAPAT activity, and immunofluorescence for thiolase and catalase. No therapeutic intervention was tested.
No curative therapy or long-term effective treatment currently exists for peroxisomal disorders. Patient-derived induced pluripotent stem cells have been generated from multiple healthy controls and patients with peroxisome biogenesis disorders, and differentiated into neural progenitors, motor neurons, and oligodendrocytes. These models have been proposed for high-content screening of chemical libraries, but no drug screening results from such libraries are reported. Separately, CRISPR/Cas9 was used to introduce PEX1 null mutations in HepG2 liver-cancer cells, and a base-editing system showed preliminary evidence that introducing or correcting the common PEX1-p.G843D mutation is possible. Further research is needed to determine whether this technology has therapeutic benefits.
What is still missing: any clinical trial testing a drug in patients with peroxisome biogenesis disorder type 3B or any other PBD subtype; a patient-derived cell line or animal model that recapitulates the specific PEX11β mutation for drug testing; and funding or trial design that would move the existing iPSC and CRISPR tools from proof-of-concept toward a therapy. Patient stratification by PEX gene and mutation severity remains unaddressed in any interventional study.
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.
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 · 2019 · 0 citations · open access
Developing novel in vitro model systems to investigate therapeutic hypotheses for peroxisome biogenesis disorders
AbstractPeroxisomes are microbody organelles present in virtually all cells of eukaryotic organisms. They play vital roles in numerous metabolic pathways including the catabolism of very long chain fatty acids (VLCFAs) as well as the biogenesis of docosahexaenoic acid (DHA) and plasmalogens. Proper assembly and function of peroxisomes is essential to human health and development. The importance of proper peroxisome function is highlighted by a number of multi-systemic disorders in humans that result from inherited mutations in peroxisome-related genes, collectively referred to as peroxisome biogenesis disorders (PBDs). Peroxisome biogenesis disorders affect the body globally, although certain organ systems that rely more heavily on peroxisome-mediated metabolism are more seriously affected, including the nervous and hepatic systems. ? Currently, because primary cell models are inaccessible due to ethical dilemmas, it is difficult to study the mechanics of PBDs in the context of specific organ systems. The most common cell-based models for PBDs are derived from patient and genetically engineered mouse fibroblasts. Although these cells have proven invaluable for screening small molecule libraries, our goal is to establish and test cell models that more closely represent affected cell-types. We hypothesized that the widely utilized HepG2 liver-cancer immortalized cell-line carrying common PBD mutations may serve as a better model for testing the effects that drugs identified as possibly therapeutic in immortalized fibroblast models may have on liver function and health and better elucidate the mechanisms by which the rescue is occurring. We used CRISPR/Cas9 gene editing to introduce PEX1 null mutations in HepG2 cells via the introduction of double-strand breaks in PEX1. We were able to successfully generate two separate HepG2 cell lines, each homozygous for null PEX1, differing slightly in their specific mutations. ? We also explored the use of a new CRISPR-Cas9 base editing system, developed in David Liu?s laboratory at Harvard University, for its ability to both introduce and correct the most common PEX1 mutation, the PEX1-p.G843D mutation. This single-base pair mutation results in a hypomorph allele with limited gene function. Using the CRISPR-Cas9 base-editing system, we have preliminary evidence that suggests both introduction and correction of PEX1-p.G843D are possible and efficient. Further research is required to investigate the potential benefits to PBD research and therapeutic endeavors that this technology may make possible.
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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