DeCure for Peroxisome biogenesis disorder 11A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 11A (Zellweger) — screening already-approved drugs against its 2-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 11A (Zellweger) maps to a 2-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 11a (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 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 2017 review states that peroxisome biogenesis disorders, including Zellweger syndrome, are autosomal recessive, impair peroxisome assembly, and cause deficiencies of peroxisomal enzymes, developmental sequelae, and progressive disabilities. The 2012 review notes that classic Zellweger syndrome is a lethal disease with no morphologically recognisable peroxisomes. The 2023 case report describes a patient diagnosed with Zellweger syndrome in the context of dysmorphism and seizures, with the disorder characterised by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. The 2012 paper on the first PEX11β patient reports that this patient presented with symptoms atypical for peroxisome biogenesis disorders, and that peroxisomes in cells from that patient appeared enlarged and undivided.
The 2004 and 2012 reviews state that the metabolic and molecular basis of most peroxisomal disorders has been resolved, and that diagnostic methods have been established. The 2017 review says diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing, and in some cases analysis of peroxisome morphology. It adds that for most patients there is a correlation between clinical severity and the effect of the mutation on PEX protein function. The 2017 review also says there are no targeted therapies.
The 2020 paper describes a lentiviral transfer plasmid expressing eGFP-PTS1 that allows stable expression and quantification of peroxisome biogenesis and peroxisome motility in Zellweger spectrum disorder and control mouse and human fibroblasts. The authors state that this tool meets the needs for in vitro peroxisome biogenesis evaluation and ZSD drug discovery. No drug screening results are reported in that paper. No abstract in this set reports any drug tested in patients or in animal models of Zellweger syndrome. No abstract reports any improvement in survival, development, or biochemical markers from any intervention.
What is still missing is any clinical trial testing a candidate therapy in patients, any drug screening that has identified a compound that restores peroxisome biogenesis in human cells, and any animal model study showing functional rescue. The 2017 review notes that improved knowledge of peroxin functions, continued characterisation of disease models, and systematic clinical studies are expected to impact treatment, but that expectation has not been met with published data.
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 Molecular Genetics · 1995 · 285 citations
Disorders of peroxisome biogenesis
AbstractThe peroxisome is a ubiquitous, subcellular organelle containing more than 50 matrix enzymes that participate in a diverse array of metabolic pathways. Failure to assemble normal peroxisomes is the cellular hallmark of Zellweger syndrome and other human disorders of peroxisome biogenesis. Identification of the genes required for peroxisome biogenesis is proceeding at a rapid pace helped immeasurably by work in other species, particularly various yeasts. The ultimate goals of this effort are to identify all of these genes and to understand how their protein products interact to produce normal appearing and functioning peroxisomes. Attainment of these goals will lead to a better understanding of the peroxisome biogenesis disorders, their pathophysiology and treatment.
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.
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.
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.
Clinical, biochemical and genetic aspects of peroxisomal disorders – an expanding group of genetic diseases in humans
AbstractZellweger syndrome (ZS) in its classic form is an autosomal recessive lethal disease characterized by the absence of morphologically recognizable peroxisomes. Detailed studies on ZS in the early 1980s have led to the discovery of a set of peroxisomal biomarkers in blood which has revolutionized our knowledge about peroxisomes and peroxisomal disorders, and formed the basis for the discovery of the group of peroxisomal diseases known at present. Peroxisomal disorders are classified into two distinct groups including the disorders of peroxisome biogenesis (group 1) and peroxisome function (group 2). The enzymatic and molecular basis of most peroxisomal disorders has been identified through the years and pre- and post-natal diagnostic methods have been established. This review describes the current state of knowledge with respect to peroxisomes and peroxisomal disorders with particular emphasis on the clinical biochemical and genetic aspects of these disorders.
PARIPEX-INDIAN JOURNAL OF RESEARCH · 2023 · 0 citations · open access
A CASE REPORT OF ZELLWEGER SYNDROME WITH GLOBAL DEVEOPMENTAL DELAY
AbstractPeroxisome biogenesis disorder are related to spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterized by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. We report a case of Zellweger syndrome, confirmed by clinical, biochemical and molecular findings, diagnosed in context of dysmorphism, and seizures
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.
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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