DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 14B — 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 14B 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 14b 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 disorder 14B is an autosomal recessive condition caused by mutations in the PEX11B gene. A 2023 case report describes a 13-year-old female adolescent of Greek origin with a novel homozygous nucleotide substitution, c.122T>A, in the PEX11B gene, which leads to premature termination of protein synthesis and impaired biogenesis of type 14B peroxisomes. Her clinical features included congenital cataract, clubfoot from infancy, mild psychomotor retardation, overweight, progressive gait unsteadiness, episodes of faecal incontinence in a dolichosigmoid setting, and non-autoimmune hypothyroidism. On examination she had furrows, lowered eyelid fissures and corners of the mouth, a deep philtrum, micrognathia, reduced muscle strength in the peripheral parts of the upper and lower limbs, absence of tendon reflexes, and atrophy of the thenar, peroneal and tibial muscles. Neurophysiological examination confirmed peripheral polyneuropathy. Neuroimaging, metabolic screening, and karyotype were normal. Both parents were heterozygous carriers of the same mutation.
Before this, only one patient with a PEX11β mutation had been reported, in a 2012 study that identified the first human case. That patient presented with symptoms atypical for peroxisome biogenesis disorders, and cells derived from the patient showed enlarged, undivided peroxisomes, consistent with the known role of PEX11 proteins in peroxisome proliferation and division. The 2012 report widened the recognised clinical and cellular spectrum of diseases associated with defective peroxisome formation. Peroxisome biogenesis disorders in general are most commonly caused by mutations in the PEX1 gene, which accounts for about two-thirds of cases, according to a 2018 review.
No treatment or intervention for peroxisome biogenesis disorder 14B is described in any of these abstracts. The 2023 case report is a single-patient genetic description, not a therapeutic trial. What is missing is any clinical trial data, any tested drug or dietary intervention, any systematic natural history study with a meaningful number of patients, and any validated biomarkers or outcome measures for this ultra-rare condition. Without funding for patient registries, longitudinal studies, and preclinical work on peroxisome biogenesis, no evidence exists to support any specific treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
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.
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.
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.
Journal of Pediatrics Perinatology and Child Health · 2023 · 2 citations · open access
A Novel Mutation (c.122T>A) of PEX11B Gene in a Female Adolescent with Congenital Cataract and Clubfoot
AbstractObjective: Peroxisome biogenesis disorder type 14B (PEX14B, OMIM #614920) is an autosomal recessive disorder characterized clinically by mild mental retardation, congenital cataract, progressive hearing loss, and polyneuropathy. We aimed to report a new mutation in a female adolescent of Greek origin with prominent clinical signs of congenital cataract and clubfoot. Material: A 134/12-year-old girl having overweight, mild psychomotor retardation, congenital cataract, clubfoot from infancy progressively worsening with accompanying unsteadiness of gait, episodes of faecal incontinence in the dolichosigmoid setting and non-autoimmune hypothyroidism was presented. On clinical examination, furrows, lowered eyelid fissures and corners of the mouth, a deep philtrum and micrognathia were noted and neurologically found reduced muscle strength in the peripheral parts of the upper and lower limbs with absence of tendon reflexes and atrophy of the thenar, peroneal and tibial muscles both, findings indicative of peripheral polyneuropathy, which was confirmed in the neurophysiological examination. Neuroimaging, metabolic control and karyotype reveled normal findings. Whole Exome Sequencing (WES) was performed. Results: The unreported nucleotide substitution c122T>A in the PEX11B gene was found in the homozygous state, causing premature termination of protein synthesis and impaired biogenesis of type 14B peroxisomes. Heterozygosity for the same mutation was found in parents. Conclusions: DNA sequencing of all genes is an excellent tool for the diagnosis of phenotypically and genetically heterogeneous conditions such as as disorders of hyperhyxosome biogenesis. The detection of new mutations helps to complete the clinical and genetic spectrum of rare diseases and constitutes a valuable learning resource for future research.
University of Southern California Digital Library · 2014 · 0 citations · open access
Development of computational tools to assist high content screening to identify drug therapies for peroxisome biogenesis disorders
AbstractPeroxisome biogenesis disorders are genetic disorders due to mutations in one or more of the PEX genes, resulting in impaired transport of peroxisomal proteins or errors in peroxisome formation. The disorder has been treated only symptomatically until recent work by Dr. Braverman?s drug screen which found potential candidates to treat this disorder. The work was done with a limited number of compounds at single concentrations. ? The collaboration of Hacia lab with NIH has resulted in the screening of the SIGMA-LOPAC library which consists of pharmacologically compounds relevant to many biological processes. About 1280 compounds at seven different concentrations has resulted in data of over 65 gigabytes and six million images. This thesis deals with the development of computational tools with quantitative and qualitative support using Java, Matlab and SQL to assist screening of new candidate drugs to treat peroxisome biogenesis 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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