DeCure for Peroxisome biogenesis disorder 12A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 12A (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 12A (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 12a (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 19 (PEX19) — PEX19 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 2WL8 · 2.05 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Peroxisome biogenesis disorder 12A (Zellweger syndrome) is an autosomal recessive lethal disease characterised by the absence of morphologically recognisable peroxisomes. The Zellweger spectrum comprises a clinical continuum from Zellweger syndrome as the most severe form, with survival up to twelve months, through neonatal adrenoleukodystrophy as an intermediate form, to infantile Morbus Refsum as the mildest variant. The disorder is caused by mutations in PEX genes encoding peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. 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 genomic rearrangement resulting in a 147 kb deletion spanning the whole of PEX13, the other an out-of-frame deletion of 14 bp. This was the first report of a PEX13 deletion.
The pathogenesis of Zellweger syndrome remains largely unknown, although patients exhibit severe pathology in multiple organs including the liver, kidney, brain, muscle, and bone. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream mitochondrial fission-fusion processes, and disruption of this regulation may cause multiple organ dysfunctions reminiscent of Zellweger syndrome. The metabolic and molecular basis of most peroxisomal disorders has been resolved, and pre- and post-natal diagnostic methods have been established. Peroxisomal biomarkers in blood have been identified.
No clinical trial data for any drug treatment in peroxisome biogenesis disorder 12A were reported in these abstracts. No survival rates, response rates, or sample sizes for any intervention were given. The abstracts are reviews and case reports; they contain no evidence of any therapeutic agent being tested in patients. What is still missing is any clinical trial testing a drug in this population, any patient stratification beyond genetic complementation groups, and funding for such trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
Frontiers in Cell and Developmental Biology · 2022 · 16 citations · open access
Control of mitochondrial dynamics and apoptotic pathways by peroxisomes
AbstractPeroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.
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.
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.
