DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 4B — 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 4B 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 4b 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
Peroxisome biogenesis disorders, including peroxisome biogenesis disorder 4B, are caused by defects in PEX genes whose products, peroxins, are essential for peroxisome assembly. The estimated incidence of PBDs is 1 in 50,000 births in America. Mutations in PEX1 account for two-thirds of PBD cases. In 2008, analysis of 11 fibroblast cell lines from PBD patients with PEX5 defects found 11 different mutations, eight of which were novel. Six of those cell lines showed a defect in both PTS1 and PTS2 protein import, while four showed a defect only in PTS1 import. The location of the mutations within the PEX5 amino acid sequence correlated with the import defect observed.
As of 2016, there was no curative therapy or long-term effective treatment available for PBDs. High-content screening of chemical libraries identified a novel group of small molecules active at the micromolar range that rescued peroxisome functions in patient cells, based on cell imaging, biochemical, and protein processing assays. Induced pluripotent stem cells were generated from primary skin fibroblasts of PBD patients and differentiated into CNS and hepatocyte cell lineages, showing peroxisomal protein defects in the derived cells. A Pex1-p.G844D mouse model was characterised as the first mouse model with hypomorphic PEX alleles, and gene expression profiling of the murine retina along with recovery of peroxisomal protein import by AAV-mediated gene expression suggested the mice could serve as a model for retinal gene therapy.
The molecular defects have been identified in nearly all peroxisomal disorders, which has facilitated diagnosis, prenatal diagnosis, and heterozygote identification. Genotype-phenotype correlations have led to a new classification system. Animal models have been developed. What remains missing is a curative therapy for patients. The small molecules identified in 2016 are still at the stage of providing tools for investigation and leads for development, not a proven treatment. No clinical trial data for any drug in peroxisome biogenesis disorder 4B is reported in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
BioEssays · 1997 · 58 citations
Peroxisome biogenesis
AbstractPeroxisomes are eukaryotic organelles that are the subcellular location of important metabolic reactions. In humans, defects in the organelle's function are often lethal. Yet, relative to other organelles, little is known about how cells maintain and propagate peroxisomes or how they direct specific sets of newly synthesized proteins to these organelles (peroxisome biogenesis/assembly). In recent years, substantial progress has been made in elucidating aspects of peroxisome biogenesis and in identifying PEX genes whose products, peroxins, are essential for one or more of these processes. The most progress has been made in understanding the mechanism by which peroxisome matrix proteins are imported into the organelles. Signal sequences responsible for targeting proteins to the organelle have been defined. Potential signal receptor proteins, a receptor docking protein and other components of the import machinery have been identified, along with insights into how they operate. These studies indicate that multiple peroxisomal protein-import mechanisms exist and that these mechanisms are novel, not simply variations of those described for other organelles.
Frontiers in bioscience · 2000 · 39 citations · open access
Molecular genetics of peroxisomal disorders
AbstractTwenty five human peroxisomal disorders have been defined at this time. They are subdivided into two major categories: 1) the disorders of peroxisome biogenesis, in which the organelle fails to form normally, and there are defects that involve multiple peroxisomal functions; and 2) disorders that affect single peroxisomal enzymes. During the last five years the molecular defects have been identified in nearly all. These recent advances have several important implications. They have facilitated diagnosis of affected patients. The improved capacity to provide prenatal diagnosis and heterozygote identification has been of great value for genetic counseling and disease prevention. Study of genotype-phenotype correlations has led to a new and more rational classification system. The identification of the molecular defects and the development of animal models have increased understanding of pathogenetic mechanisms, and have led to novel therapeutic approaches.
International Journal of Biomedical Science · 2006 · 38 citations
Peroxisomes and Disease - an Overview
AbstractPeroxisomes are indispensable for human health and development. They represent ubiquitous subcellular organelles which compartmentalize enzymes responsible for several crucial metabolic processes such as β-oxidation of specific fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species. Peroxisomes are highly flexible organelles that rapidly assemble, multiply and degrade in response to metabolic needs. Basic research on the biogenesis of peroxisomes and their metabolic functions have improved our knowledge about their crucial role in several inherited disorders and in other pathophysiological conditions. The goal of this review is to give a comprehensive overview of the role of peroxisomes in disease. Besides the genetic peroxisomal disorders in humans, the role of peroxisomes in carcinogenesis and in situations related to oxidative stress such as inflammation, ischemia-reperfusion, and diabetes will be addressed.
Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines
AbstractProteins destined for the peroxisomal matrix are targeted by virtue of a peroxisomal targeting sequence type 1 (PTS1) or type 2 (PTS2). In humans, targeting of either class of proteins relies on a cytosolic receptor protein encoded by the PEX5 gene. Alternative splicing of PEX5 results in two protein variants, PEX5S and PEX5L. PEX5S is exclusively involved in PTS1 protein import, whereas PEX5L mediates the import of both PTS1 and PTS2 proteins. Genetic complementation testing with over 500 different fibroblast cell lines from patients diagnosed with a peroxisome biogenesis disorder (PBD) identified 11 cell lines with a defect in PEX5. The aim of this study was to characterize these cell lines at a biochemical and genetic level. To this end, the cultured fibroblasts were analyzed for very long chain fatty acid (VLCFA) concentrations, peroxisomal beta-and alpha-oxidation, dihydroxyacetone-phosphate acyltransferase (DHAPAT) activity, peroxisomal thiolase, and catalase immunofluorescence. Mutation analysis of the PEX5 gene revealed 11 different mutations, eight of which are novel. PTS1- and PTS2-protein import capacity was assessed by transfection of the cells with green fluorescent protein (GFP) tagged with either PTS1 or PTS2. Six cell lines showed a defect in both PTS1 and PTS2 protein import, whereas four cell lines only showed a defect in PTS1 protein import. The location of the different mutations within the PEX5 amino acid sequence correlates rather well with the peroxisomal protein import defect observed in the cell lines.
Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder
AbstractOBJECTIVE: To determine the enzymatic defect in a patient with ataxia, dysarthric speech, dry skin, hypotonia, and absent reflexes. The patient was previously diagnosed with a presumed deficiency of trihydroxycholestanoyl-CoA oxidase. BACKGROUND: Peroxisomes harbor a variety of metabolic functions, including fatty acid beta-oxidation, etherphospholipid biosynthesis, phytanic acid alpha-oxidation, and L-pipecolic acid oxidation. This patient was previously described with an isolated peroxisomal beta-oxidation defect caused by a deficiency of the enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of accumulating metabolites. METHODS: Measurement of beta-oxidation enzymes, peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts, and DNA analysis of the PEX12 gene were performed. RESULTS: An isolated beta-oxidation defect in this patient was excluded by measurement of the various beta-oxidation enzymes. The authors found that the patient had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene, although all peroxisomal functions in cultured skin fibroblasts were normal. CONCLUSIONS: The absence of clear peroxisomal abnormalities in the patient's fibroblasts, including a normal peroxisomal localization of catalase, implies that even when all peroxisomal functions in fibroblasts are normal, a peroxisome biogenesis disorder cannot be fully excluded, and further studies may be needed. In addition, the authors' findings imply that there is no longer evidence for the existence of trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity.
Topics in Magnetic Resonance Imaging · 2018 · 15 citations
Clinical and Neuroimaging Spectrum of Peroxisomal Disorders
AbstractPeroxisomes play vital roles in a broad spectrum of cellular metabolic pathways. Defects in genes encoding peroxisomal proteins can result in a wide array of disorders, depending upon the metabolic pathways affected. These disorders can be broadly classified into 2 main groups; peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies. Peroxisomal enzyme deficiencies are result of dysfunction of a specific metabolic pathway, while PBDs are due to generalized peroxisomal dysfunction. Mutations in PEX1 gene are the most common cause of PBDs, accounting for two-thirds of cases. Peroxisomal fission defects is a recently recognized entity, included under the subgroup of PBDs. The aim of this article is to provide a comprehensive review on the clinical and neuroimaging spectrum of peroxisomal disorders.
University of Southern California Digital Library · 2016 · 0 citations · open access
Development of targeted therapies for peroxisome biogenesis disorders
AbstractPeroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous rare metabolic diseases caused by defects in peroxins, proteins encoded by PEX genes that function in peroxisome biogenesis. PBDs display an autosomal recessive mode of transmission with an estimated incidence of 1 in 50,000 births in America. Although the genetic basis of PBDs is well understood, there is currently no curative therapy or long-term effective treatment available. ? In this dissertation, I described the identification and characterization of small molecules that enhance peroxisome assembly and function in PBD patient cells through high-content screening (HCS) of chemical libraries. Our therapeutic hypothesis is that the rescue of peroxisome assembly and functions will be of therapeutic benefit to individuals with peroxisome biogenesis disorders. We uncovered a novel group of compounds active at the micromolar range that rescued peroxisome functions in patient cells based on cell imaging, biochemical, and protein processing assays. Overall, the novel bioactive small molecules we identified could provide tools for investigating peroxisome biogenesis and novel leads for the development of targeted small molecule therapies, and the new cellular and animal models can be the next generation screening tools to discover and characterize more active compounds. ? In addition, I describe the development of new model systems of PBDs, including induced pluripotent stem cells (iPSCs), HepG2 cells and mice. We generated iPSCs from primary skin fibroblasts of PBD patients and differentiated them into central nervous system (CNS) and hepatocyte cell lineages and showed peroxisomal protein defects of the derived cells. We also generated and characterized HepG2 PEX1 mutant cell lines with peroxisome assembly defects. Finally, I also participated in the characterization of the Pex1-p.G844D mouse which is the first mouse model with hypomorphic PEX alleles and thus better disease model for PBD patients with milder clinical features. Gene expression profiling of the murine retina and the recovery of peroxisomal protein import by adeno-associated virus (AAV)-mediated gene expression suggested that the mice can serve as a powerful model system for investigating retinal gene therapy. Overall, These iPSC, iPSC-derived cells, murine model skin fibroblast and HepG2 cells carrying common PEX1 mutations can have future applications for chemical library screening for candidate drugs that directly address the cell type specificity of disease and the nature of the mutations found in the patient population.
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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