DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 11B — 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 modulePeroxisome biogenesis disorder 11B 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 peroxisome biogenesis disorder 11b 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 13 (PEX13) — PEX13 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 7Z0J · 2.3 Å · ligand none (apo structure). 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 phenotypes. Peroxisomes in cells from this patient appeared enlarged and undivided, consistent with the role of PEX11 proteins in peroxisome proliferation and division. Before this, only the PEX11 family among human PEX genes had not been associated with human disease. The patient presented with symptoms atypical for peroxisome biogenesis disorders.
Peroxisome biogenesis disorders are autosomal recessive, with an estimated incidence of 1 in 50,000 births in America. There is no curative therapy or long-term effective treatment. In 2016, high-content screening of chemical libraries identified small molecules active at micromolar range that rescued peroxisome functions in patient cells, based on cell imaging, biochemical, and protein processing assays. The same work generated induced pluripotent stem cells from PBD patient fibroblasts, differentiated them into central nervous system and hepatocyte cell lineages, and showed peroxisomal protein defects in the derived cells. A Pex1-p.G844D mouse model was characterised, and gene expression profiling of the murine retina along with recovery of peroxisomal protein import by adeno-associated virus-mediated gene expression suggested the mice could serve as a model for retinal gene therapy.
In 2019, CRISPR/Cas9 gene editing was used to introduce PEX1 null mutations in HepG2 liver-cancer cells, generating two homozygous null cell lines. Preliminary evidence using a CRISPR-Cas9 base editing system suggested that both introduction and correction of the common PEX1-p.G843D mutation are possible and efficient. However, further research is required to investigate potential benefits. The 2017 review notes that for most patients there is a correlation between clinical severity and the effect of the mutation on PEX protein function, and that the full spectrum of these disorders remains to be identified. What is still missing are targeted therapies that have reached patients, systematic clinical studies, and validated models that represent affected organ systems more closely than fibroblasts — the HepG2 and iPSC models are early steps, but funding for large-scale screening, rigorous trial design, and patient stratification by specific PEX mutation and residual function remain 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.
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.
AbstractThe peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to deficiencies of peroxisomal enzymes, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the coordinated action of multiple PEX proteins, or peroxins, encoded by PEX genes. There are two main groups of PBD: Zellweger spectrum disorder, due to defects in any one of 13 PEX genes, and Rhizomelic Chondrodysplasia Punctata spectrum, mainly due to defects in PEX7. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing and, in some cases, analysis of peroxisome morphology and more detailed studies of peroxisome biology. Recent advancements in diagnosis have expanded the phenotypes observed, indicating that the full spectrum of these disorders remains to be identified. Although there are no targeted therapies, improved knowledge of peroxin functions, continued characterization of disease models, and systematic clinical studies are expected to impact treatment in the near future.
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.
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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