DeCure for Peroxisome biogenesis disorder 4A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 4A (Zellweger) — screening already-approved drugs against its 4-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 4A (Zellweger) maps to a 4-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 4a (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 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 1999 study of a single Zellweger syndrome patient (PBD061) identified inactivating mutations in the PEX16 gene, which codes for a novel integral peroxisomal membrane protein. In this patient’s cells, expression of PEX16 restored peroxisome formation and peroxisomal membrane protein import within 2–3 hours, followed by matrix protein import. This finding contradicted the then-prevailing view that peroxisomes arise only from division of preexisting peroxisomes, and the authors proposed two pathways: PEX11-mediated division and PEX16-mediated formation from scratch.
A 2006 review states that the Zellweger spectrum includes Zellweger syndrome as the most severe form, with survival up to twelve months, along with neonatal adrenoleukodystrophy and infantile Morbus Refsum. A 2022 review notes that peroxisomes regulate intrinsic apoptotic pathways and mitochondrial fission-fusion processes, and that disruption of these processes may cause multiple organ dysfunctions reminiscent of Zellweger syndrome. However, the review also states that the pathogenesis of Zellweger syndrome remains largely unknown.
No drug treatment is tested or proposed in any of these abstracts. No clinical trial data, no survival or response rates, and no patient outcomes beyond the single PBD061 case are reported. What is missing is any drug candidate, any preclinical model of drug effect, any patient stratification strategy, and any funding for a treatment development programme.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Cell Biology · 1999 · 243 citations · open access
Peroxisome Synthesis in the Absence of Preexisting Peroxisomes
AbstractZellweger syndrome and related diseases are caused by defective import of peroxisomal matrix proteins. In all previously reported Zellweger syndrome cell lines the defect could be assigned to the matrix protein import pathway since peroxisome membranes were present, and import of integral peroxisomal membrane proteins was normal. However, we report here a Zellweger syndrome patient (PBD061) with an unusual cellular phenotype, an inability to import peroxisomal membrane proteins. We also identified human PEX16, a novel integral peroxisomal membrane protein, and found that PBD061 had inactivating mutations in the PEX16 gene. Previous studies have suggested that peroxisomes arise from preexisting peroxisomes but we find that expression of PEX16 restores the formation of new peroxisomes in PBD061 cells. Peroxisome synthesis and peroxisomal membrane protein import could be detected within 2-3 h of PEX16 injection and was followed by matrix protein import. These results demonstrate that peroxisomes do not necessarily arise from division of preexisting peroxisomes. We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes.
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 diseases of children · 1988 · 36 citations
Peroxisomal Disorders
AbstractThe peroxisomal disorders are a group of inherited metabolic diseases with serious clinical sequelae. The number of recognized peroxisomal disorders has increased substantially since 1973, when an absence of peroxisomes was observed in patients with the cerebro-hepato-renal (Zellweger's) syndrome. More subtle peroxisomal dysfunction is now recognized, including that deriving from single peroxisomal enzymes. Peroxisomal disorders are relatively rare. However, these disorders assume importance because of our growing ability to relate clinical sequelae to specific enzymatic and biochemical deficits, because some of these disorders can now be identified prenatally and their recurrence can be prevented, and because therapies are rapidly evolving. We reviewed these disorders in light of increasing understanding of the biochemistry of the peroxisome.
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.
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.
Peroxisomal Biogenesis: Genetic Disorders Reveal the Mechanisms
AbstractPeroxisome biogenesis: challenging the paradigm 2.1 Zellweger's Syndrome (ZS) as the prototypic Peroxisome Biogenesis Disorder (PBD) ZS is characterized by craniofacial dysmorphia, neurological impairment, severe metabolic disturbances and neonatal death, caused either by complete absence of peroxisomes or by defects in protein importation into peroxisomal membrane precursors From the clinical point of view, a severity spectrum of these disorders has been established (SZ spectrum), including Neonatal Adrenoleukodystrophy (NALD; MIM 202370), Infantile Refsum disease (IRD; MIM] 266510) and SZ (ZS; MIM 214100) as the most severe (8). Initial studies in liver biopsies of ZS patients failed to find evidence of peroxisomal components and thus led to the notion that ZS patients lack peroxisomes (9). Later studies in Zellweger fibroblasts detected membranes containing peroxisomal membrane proteins (PMPs) but that lack most of the matrix proteins and were called "peroxisomal membrane ghosts" (10-12). Since then, a defect in the peroxisomal importing machinery for matrix proteins became www.intechopen.com Advances in the Study of Genetic Disorders 322 apparent as a crucial cause of ZS. The fibroblasts from these patients provided a genetic model system for studying the mechanisms of peroxisomal biogenesis (1), while the incorporation of genetic tools in yeast allowed complementary and more detailed approaches (13-15).
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.
