DeCure for Peroxisome biogenesis disorder 10A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 10A (Zellweger) — 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 10A (Zellweger) 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 10a (zellweger) 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 3 (PEX3) — PEX3 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 3MK4 · 2.42 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Peroxisome biogenesis disorders are a group of autosomal recessive conditions in which peroxisome assembly is impaired, leading to deficiencies of peroxisomal enzymes, complex developmental sequelae and progressive disabilities. Zellweger syndrome is the prototype and most severe form, with survival up to twelve months. The disorders are caused by mutations in any of 13 PEX genes encoding peroxins; for most patients there is a correlation between clinical severity and the effect of the mutation on PEX protein function. Mutations in PEX13 are among the least common causes, with only three mutations reported by 2009. Two infants with classical Zellweger syndrome were found to harbour novel PEX13 mutations: one had a 147 kb deletion spanning the whole of PEX13, the other an out-of-frame 14 bp deletion. That was the first report of a PEX13 deletion.
Diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing, and in some cases analysis of peroxisome morphology. Recent advancements in diagnosis have expanded the phenotypes observed, indicating that the full spectrum of these disorders remains to be identified. There are no targeted therapies. In vitro drug screening is part of the quest for a cure by restoring peroxisome biogenesis in Zellweger spectrum disorder cell models. A third-generation lentiviral transfer plasmid expressing enhanced green fluorescent protein fused to a peroxisome targeting signal 1 (eGFP-PTS1) was developed to quantify peroxisome biogenesis and peroxisome motility in Zellweger spectrum disorder and control mouse and human fibroblasts. Stable eGFP-PTS1 expression was confirmed along cell passages, and the eGFP signal distinguished Zellweger spectrum disorder from control transduced cells. The tool was deposited on Addgene for use in in vitro peroxisome biogenesis evaluation and drug discovery.
No drug has been tested in any clinical trial for peroxisome biogenesis disorder 10A or any Zellweger spectrum disorder. The 2020 lentiviral reporter tool is a method for cell-based screening, not a therapy. What is still missing is any funded drug development programme, a clinical trial design that accounts for the rarity and severity of the disease, and patient stratification by residual peroxin function, which the genotype-phenotype correlation suggests would be necessary to interpret any future treatment effect.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Orphanet Journal of Rare Diseases · 2015 · 238 citations · open access
Zellweger spectrum disorders: clinical overview and management approach
AbstractZellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.
American Journal of Medical Genetics Part A · 2004 · 173 citations
Metabolic and molecular basis of peroxisomal disorders: A review
AbstractThe group of peroxisomal disorders now includes 17 different disorders with Zellweger syndrome as prototype. Thanks to the explosion of new information about the functions and biogenesis of peroxisomes, the metabolic and molecular basis of most of the peroxisomal disorders has been resolved. A review of peroxisomal disorders is provided in this paper.
American Journal of Medical Genetics Part A · 2009 · 18 citations
Zellweger syndrome caused by PEX13 deficiency: Report of two novel mutations
AbstractPeroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they are characterized by a spectrum of dysmorphia, neurological, liver, and other organ involvement. To date, mutations in 13 PEX genes encoding peroxins have been identified in patients with peroxisomal biogenesis disorders. Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among the least common causes of peroxisomal biogenesis disorders with only three mutations reported so far. Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders. We show that they harbor two novel mutations in PEX13. One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp. This represents the first report of a PEX13 deletion and suggests that further work is needed to examine the frequency of PEX13 mutations among Arab patients with peroxisomal biogenesis disorders.
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.
Histochemistry and Cell Biology · 2020 · 6 citations · open access
Accurate and live peroxisome biogenesis evaluation achieved by lentiviral expression of a green fluorescent protein fused to a peroxisome targeting signal 1
AbstractPeroxisomes are ubiquitous organelles formed by peroxisome biogenesis (PB). During PB, peroxisomal matrix proteins harboring a peroxisome targeting signal (PTS) are imported inside peroxisomes by peroxins, encoded by PEX genes. Genetic alterations in PEX genes lead to a spectrum of incurable diseases called Zellweger spectrum disorders (ZSD). In vitro drug screening is part of the quest for a cure in ZSD by restoring PB in ZSD cell models. In vitro PB evaluation is commonly achieved by immunofluorescent staining or transient peroxisome fluorescent reporter expression. Both techniques have several drawbacks (cost, time-consuming technique, etc.) which we overcame by developing a third-generation lentiviral transfer plasmid expressing an enhanced green fluorescent protein fused to PTS1 (eGFP-PTS1). By eGFP-PTS1 lentiviral transduction, we quantified PB and peroxisome motility in ZSD and control mouse and human fibroblasts. We confirmed the stable eGFP-PTS1 expression along cell passages. eGFP signal analysis distinguished ZSD from control eGFP-PTS1-transduced cells. Live eGFP-PTS1 transduced cells imaging quantified peroxisomes motility. In conclusion, we developed a lentiviral transfer plasmid allowing stable eGFP-PTS1 expression to study PB (deposited on Addgene: #133282). This tool meets the needs for in vitro PB evaluation and ZSD drug discovery.
Rational diagnostic for Zellweger Syndrome and other peroxisomal biogenesis defects
AbstractObjective: Peroxisomal biogenesis defects (PBD) are a clinically and genetically heterogeneous disease entity. The Zellweger spectrum comprises a clinical continuum from Zellweger syndrome as the most severe form of disease with a survival up to twelve months, over neonatal adrenoleukodystrophy as an intermediate form, to infantile Morbus Refsum as the mildest variant.
AbstractA group of conditions characterized by impairment of peroxisome assembly and metabolic pathways confined to this organelle, caused by mutation(s) in the peroxin (PEX) gene family.Phenotypically, they manifest as Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP1), the latter a distinct peroxisome biogenesis disorder phenotype.ZS, NALD, and IRD have multiple complementation groups and form a spectrum of diseases with overlapping features.
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.
