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At least 19 recordsLinked to original sources
PubMed2026

Zebrafish as a versatile model in biomedical research, from disease modeling to regenerative medicine: a review.

Zebrafish are an effective animal model widely utilized in biomedical research. They are known for their rapid reproduction and substantial genetic similarity to humans. Their transparent embryos directly enable the visualization of developmental processes and disease progression. This makes zebrafish invaluable for studying a broad range of human diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Compared with other vertebrate models, zebrafish offer several advantages, including ease of genome editing, cost-effective maintenance, and suitability for high-throughput drug screening. Recent advancements have expanded the use of zebrafish in disease modeling and regenerative medicine, providing deeper insights into the genetic and cellular mechanisms underlying human pathologies. Zebrafish provide a robust platform for evaluating the safety, efficacy, and regenerative potential of both natural and synthetic biomaterials, including hydroxyapatite, bioactive glass nanoparticles, and bioceramics. This capability facilitates the creation of artificial tissues that closely resemble native structures. Additionally, integrating artificial intelligence technologies has improved automated data analysis and phenotyping in zebrafish studies, enhancing both accuracy and throughput. This review highlights current applications of zebrafish in disease modeling, drug discovery, regenerative medicine, and biomaterial assessment, emphasizing their evolving role as a versatile preclinical platform supported by advanced genetic and computational tools.

Animals↗
PubMed2026

A Landscape of Drosophila melanogaster Disease Models: From Genetic Platforms to Cross-Disease Mechanisms and Translational Research.

Modeling human diseases using the fruit fly (Drosophila melanogaster) has established itself as a cornerstone of functional genomics and preclinical medicine. Despite its anatomical simplicity, the Drosophila genome shares remarkable functional conservation with human disease-related genes, enabling the study of complex physiological traits through accessible tissue models. Furthermore, beyond individual disease models, we propose a framework demonstrating how these diseases converge at common molecular centers, such as the breakdown of protein homeostasis, mitochondrial dysfunction, chronic inflammation, and organ-to-organ communication. Finally, we discuss strategies for integrating the Drosophila platform into drug development pipelines and establishing standards to enhance inter-laboratory reproducibility. Overall, this review highlights the enduring value of fruit flies as a model system, particularly when combined with AI-omics approaches to transform complex biological datasets into actionable therapeutic strategies.

Drosophila↗
PubMed2025

Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

Humans↗
PubMed2026

Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly processed newly generated Hi-C data from iPSC-derived neurons and neurons isolated from the human postmortem brain, together with previously published data sets comprising 228 human and 89 mouse Hi-C and snm3C-seq samples from different cell subtypes. These data were merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain the chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal data sets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.

Journal Article↗
PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗
PubMed2025

Hierarchical Multi-Label Classification With Gene-Environment Interactions in Disease Modeling.

In biomedical studies, gene-environment (G-E) interactions have been demonstrated to have important implications for analyzing disease outcomes beyond the main G and main E effects. Many approaches have been developed for G-E interaction analysis, yielding important findings. However, hierarchical multi-label classification, which provides insightful information on disease outcomes, remains unexplored in G-E analysis literature. Moreover, unlabeled data are commonly observed in practical settings but omitted by many existing methods of hierarchical multi-label classification. In this study, we consider a semi-supervised scenario and develop a novel approach for the two-layer hierarchical response with G-E interactions. A two-step penalized estimation is then proposed using an efficient expectation-maximization (EM) algorithm. Simulation shows that it has superior performance in classification and feature selection. The analysis of The Cancer Genome Atlas (TCGA) data on lung cancer demonstrates the practical utility of the proposed method. Overall, this study can fill the important knowledge gap in G-E interaction analysis by providing a widely applicable framework for hierarchical multi-label classification of complex disease outcomes.

Humans↗
PubMed2025

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer's Disease Model.

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.

Alzheimer’s disease↗
PubMed2026

CRISPR/Cas9-mediated editing of ERCC6 in iPSCs: A disease model for Cockayne Syndrome type B.

Cockayne Syndrome type B (CSB) is caused by mutations in the ERCC6 gene, which encodes a key protein involved in transcription-coupled nucleotide excision repair (TC-NER) and chromatin remodeling. Deficiency in CSB leads to defective transcriptional recovery after DNA damage, oxidative stress accumulation, and progressive neurodegeneration. In this work, we generated a CRISPR/Cas9-engineered human induced pluripotent stem cell (iPSC) line, IUFi004-A-12, carrying a homozygous mutation in ERCC6 causing a premature stop codon in its 10th exon. The modified iPSCs displayed normal morphology, expressed pluripotency markers, and differentiated into all three germ layers. This model enables mechanistic studies of CSB dysfunction and facilitates therapeutic development for Cockayne Syndrome.

Humans↗
PubMed2025

High-Sensitivity Top-Down Proteomics Reveals Enhanced Maturation of Micropatterned Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for disease modeling, drug discovery, and precision medicine, yet their utility is often limited by their immature phenotype. One promising maturation strategy involves using micropatterned substrates that mimic native cardiomyocytes' organizational growth and stiffness. However, the maturity of this model has not fully been assessed, and there is currently no method to extract proteins from micropatterned hiPSC-CMs for top-down proteomic analysis. Herein, we present a high-sensitivity protein extraction protocol for top-down proteomic analysis of hiPSC-CMs. Through this method, we assessed the maturation of micropatterned hiPSC-CMs compared to traditional monoculture and coculture monolayers at the proteoform level. We found that micropatterned hiPSC-CMs display molecular signatures of cardiomyocyte maturation including increased expression of ventricular myosin light chain isoforms, reduced expression of the fetal troponin T isoform, and decreased phosphorylation of alpha-tropomyosin. This high-sensitivity approach enables robust top-down proteomics from limited, heterogeneous cell populations and identifies the micropattern hiPSC-CM as a more adult-like CM model, broadening the utility of structured culture systems for cardiac disease modeling and translational research. Source data for this manuscript are available via MassIVE repository at massive.ucsd.edu with identifier: MSV000097864.

Myocytes, Cardiac↗
PubMed2026

Establishment of induced pluripotent stem cell line TRNDi045-A-38 carrying homozygous DOK7-related Congenital Myasthenia patient-mutation knock-in variant from parental KOLF2.1J.

DOK7-related Congenital Myasthenic Syndrome (CMS) is a rare genetic neuromuscular junction disorder. This is one of the most common of the recessive forms of CMS, often presenting with more static proximal weakness (hence also referred to as limb girdle CMS). Whole-genome sequencing of affected patients implicates frameshift duplication mutations in DOK7 as drivers of impaired neuromuscular-junction signaling. In this study, we generated a human induced pluripotent stem cell (hiPSC) line TRNDi045-A-38 from the KOLF2.1J reference line, engineered to carry homozygous DOK7 c.1124_1127dupTGCC mutation knock-in using CRISPR/Cas9. This iPSC line could be used for in vitro disease modeling to study disease pathophysiology and for therapeutic development.

Humans↗
PubMed2025

Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson's disease.

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.

Journal Article↗
PubMed2026

Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development.

Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by ≥ 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Müller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.

Journal Article↗
PubMed2025

Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.

Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.

Nephritis, Hereditary↗
PubMed2025

Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism.

BACKGROUND: Seven female individuals with multiple congenital anomalies, developmental delay and/or intellectual disability have been found to have a genetic variant of uncertain significance in the mediator complex subunit 12 gene (MED12 c.3412C>T, p.Arg1138Trp). The functional consequence of this genetic variant in disease is undetermined, and insight into disease mechanism is required. METHODS: We identified a de novo MED12 p.Arg1138Trp variant in a female patient and compared disease phenotypes with six female individuals identified in the literature. To investigate affected biological pathways, we derived two induced pluripotent stem cell (iPSC) lines from the patient: one expressing wildtype MED12 and the other expressing the MED12 p.Arg1138Trp variant. We performed neural disease modelling, transcriptomics and protein analysis, comparing healthy and variant cells. RESULTS: When comparing the two cell lines, we identified altered gene expression in neural cells expressing the variant, including genes regulating RNA polymerase II activity, transcription, pre-mRNA processing, and neural development. We also noted a decrease in MED12L expression. Pathway analysis indicated temporal delays in axon development, forebrain differentiation, and neural cell specification with significant upregulation of pre-ribosome complex gene pathways. CONCLUSION: In a human neural model, expression of MED12 p.Arg1138Trp altered neural cell development and dysregulated the pre-ribosome complex providing functional evidence of disease aetiology and mechanism in MED12-related disorders.

Humans↗
PubMed2025

Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Journal Article↗
PubMed2025

CRISPR as a Tool to Uncover Gene Function in Polycystic Ovary Syndrome: A Literature Review of Experimental Models Targeting Ovarian and Metabolic Genes.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities such as hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, and is frequently accompanied by metabolic disturbances such as insulin resistance, obesity and dyslipidemia. Genome-wide association studies (GWASs) have identified several susceptibility loci, yet little is known about their functional implications. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) has emerged as a powerful gene editing tool in bridging this gap by allowing researchers to directly target candidate genes in ovarian and metabolic pathways. For instance, experimental models have highlighted the role of CYP17A1 and DENND1A.V2 in androgen excess, anti-Müllerian hormone (AMH) in follicular arrest, and insulin receptor substrate 1 (IRS1) and PPARγ in insulin signaling and adipogenesis. To highlight the multifactorial nature of PCOS, animal models, including zebrafish and rodents, have been used to reveal interactions between reproductive and metabolic phenotypes. Nevertheless, most studies remain restricted to single-gene models, and dual-gene models or combined gene editing and hormonal induction models remain underexplored. Future research integrating precision editing, multi-omic platforms, and patient-derived organoids may provide more accurate disease models and novel therapeutic strategies.

Polycystic Ovary Syndrome↗
PubMed2025

Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.

Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.

Animals↗
PubMed2026

Advances in organoids for personalized medicine: from technological development to clinical application.

Organoids, three-dimensional cell culture models derived from patient tissues or stem cells, have emerged as a cutting-edge technology in personalized medicine, owing to their remarkable ability to closely recapitulate in vivo tissue architecture and function. This review provides a comprehensive overview of the technological evolution and construction methodologies of organoids, highlighting their significant applications in oncology, genetic disorders, infectious diseases, and drug screening. This review examines how organoids enable precision medicine by preserving genomic fidelity, predicting drug sensitivity, and creating disease models via gene editing. Despite these advances, organoid technology faces several technical challenges that impede its full clinical translation. Addressing these obstacles is critical for realizing the potential of organoids in individualized therapeutic strategies. This article aims to delineate current progress and future directions in organoid research, furnishing a theoretical foundation and guiding future investigations towards enhancing personalized treatment paradigms.

disease modeling↗