DeCure for Peroxisome biogenesis disorder 8A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 8A (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 8A (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 8a (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.
What the evidence adds up to
In 1999, researchers examined fibroblasts from patients across seven known complementation groups of peroxisome biogenesis disorders, including Zellweger syndrome. They found that all patient cells still formed a minimal peroxisomal structure, but in cells defective in the PEX1, PEX5, PEX12, PEX6, PEX10, and PEX2 genes — all of which impair import of type-1 peroxisomal targeting signal (PTS1) proteins — peroxisome abundance was reduced fivefold. Cells mutated in PEX7, which only impairs type-2 targeting signal import, showed normal peroxisome numbers. A fivefold reduction was also seen in cells lacking either of two PTS1-targeted beta-oxidation enzymes, acyl-CoA oxidase and 2-enoyl-CoA hydratase/D-3-hydroxyacyl-CoA dehydrogenase, suggesting that the loss of peroxisomes in these disorders may be driven by failure to import those enzymes, and that peroxisomal beta-oxidation activity itself may regulate organelle abundance.
A 2020 review describes peroxisome biogenesis disorders as a group of conditions caused by mutations in the PEX gene family, impairing peroxisome assembly and the metabolic pathways confined to the organelle. The phenotypic spectrum includes Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata, with overlapping features and multiple complementation groups.
A 2021 study used a high-throughput screen of FDA-approved compounds on human fibroblast cells carrying the mild PEX1G843D variant, the most common mild Zellweger syndrome spectrum mutation. The screen identified the nitric oxide donor S-nitrosoglutathione (GSNO) as a compound that improved peroxisome function and biogenesis. In those mutant fibroblasts, GSNO increased both peroxisome number and function. In a humanised Drosophila model carrying the same PEX1G843D mutation, GSNO treatment led to increased survival and longer lifespan. The authors state that GSNO is a strong candidate for translation to clinical trials for mild PBD-ZSS.
No clinical trial of GSNO in any peroxisome biogenesis disorder has been reported. The 2021 study was limited to cell culture and a Drosophila model; no data exist in human patients. What is missing is funding for a phase 1 or phase 2 trial, a defined dosing regimen for humans, and any evidence of whether the effect would be meaningful in the more severe Zellweger syndrome forms or only in the mild PEX1G843D subgroup.
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 Cell Science · 1999 · 143 citations
Metabolic control of peroxisome abundance
AbstractZellweger syndrome and related disorders represent a group of lethal, genetically heterogeneous diseases. These peroxisome biogenesis disorders (PBDs) are characterized by defective peroxisomal matrix protein import and comprise at least 10 complementation groups. The genes defective in seven of these groups and more than 90% of PBD patients are now known. Here we examine the distribution of peroxisomal membrane proteins in fibroblasts from PBD patients representing the seven complementation groups for which the mutant gene is known. Peroxisomes were detected in all PBD cells, indicating that the ability to form a minimal peroxisomal structure is not blocked in these mutants. We also observed that peroxisome abundance was reduced fivefold in PBD cells that are defective in the PEX1, PEX5, PEX12, PEX6, PEX10, and PEX2 genes. These cell lines all display a defect in the import of proteins with the type-1 peroxisomal targeting signal (PTS1). In contrast, peroxisome abundance was unaffected in cells that are mutated in PEX7 and are defective only in the import of proteins with the type-2 peroxisomal targeting signal. Interestingly, a fivefold reduction in peroxisome abundance was also observed for cells lacking either of two PTS1-targeted peroxisomal beta-oxidation enzymes, acyl-CoA oxidase and 2-enoyl-CoA hydratase/D-3-hydroxyacyl-CoA dehydrogenase. These results indicate that reduced peroxisome abundance in PBD cells may be caused by their inability to import these PTS1-containing enzymes. Furthermore, the fact that peroxisome abundance is influenced by peroxisomal 105-oxidation activities suggests that there may be metabolic control of peroxisome abundance.
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.
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.
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.
Table_2_The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts.pdf
Abstract<p>Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.</p>
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.
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.
