> From Zebrafish to the Clinic

From Zebrafish to the Clinic

Zebrafish Models Driving Human Therapies

Zebrafish models of human disease have become powerful tools in preclinical drug discovery, bridging the gap between early-stage research and clinical development. Once primarily used in developmental biology, zebrafish are now instrumental in identifying, validating, and accelerating candidate therapies for a broad range of human diseases.

Numerous drug treatments currently in clinical use—or undergoing clinical trials—originated from zebrafish-based research. These models provide high-throughput, in vivo insights that complement traditional mammalian systems, enabling faster, cost-effective identification of effective compounds.

Explore the publications below to discover how zebrafish data have directly contributed to clinical advancements across oncology, neurology, rare genetic disorders, hematology, and more.

Visualizing engrafted human cancer and therapy responses in immunodeficient zebrafish.

PMC6570580

Indication: Cancer (Ewing’s Sarcoma; OMIM: 612219)

Clinical Trial: Phase I, NCT01858168

Drug: Olaparib plus temozolomide

Zebrafish Screening Assay: Adult patient-derived xenograft (PDX) and xenograft models

Reported observations: Zebrafish robustly engraft a wide array of human cancers at 37°C that grow with similar kinetics and have similar histology as those engrafted into NSG mice.

Preclinical Animal Models for Dravet Syndrome: Seizure Phenotypes, Comorbidities and Drug Screening.

PMC5994396

Indication: Epilepsy (Dravet syndrome; OMIM: 607208)

Clinical Trial: Phase II, NCT04462770

Drug: Clemizole (EPX-100)and clemizole derivatives (EPX-101,
EPX-102, EPX-103)

Zebrafish Screening Assay: Rescue of seizures in scn1lab mutant

Reported observations: Given the evidence that the zebrafish scn1labs552 model recapitulates salient genetic, behavioral, electrophysiological phenotypes observed in DS patients, and has been pharmacological validated against known AEDs, this model appears ideal for screening compound libraries for antiepileptic activity.

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.

PMC5752378

Indication: Neurodegen (amyotrophic lateral sclerosis; OMIM: 105400)

Clinical Trial: Phase I, NCT03272503

Drug: Pimozide

Zebrafish Screening Assay: Blockade of T-type Ca2+ channels to stabilize neuromuscular transmission

Reported observations: We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice.

Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death.

PMC2265478

Indication: Deafness (antibiotic-induced hearing loss, OMIM: 580000)

Clinical Trial: Phase II, NCT05730283

Drug: ORC-13361

Zebrafish Screening Assay: Protection of lateral line hair cells from cisplatin and aminoglycoside

Reported observations: We selected compound 90 as our lead compound for full pre-clinical evaluation based on its superior protective activity in the zebrafish assay.

Zebrafish Models of Diamond-Blackfan Anemia: A Tool for Understanding the Disease Pathogenesis and Drug Discovery.

PMC6958429

Indication: Blood disease (Diamond Blackfan anemia; OMIM: 105650)

Clinical Trial: Phase I/Phase II: NCT01362595, NCT01464164, NCT03966053

Drug: l-leucine, Sotatercept, Trifluoperazine

Zebrafish Screening Assay: Rescue of anaemia in rsp19 mutants

Reported observations: (1) Treatment of rps19-knockdown zebrafish with l-leucine improved the anemia and developmental defects associated with DBA. (2) We investigated the ability of the murine ortholog of sotatercept (RAP-011) to restore erythroid levels in zebrafish models of DBA. (3) A chemical screen using zebrafish rps29-/- embryos identified several calmodulin (CaM) inhibitors that can rescue hemoglobin levels in mutant embryos.

NANS-mediated synthesis of sialic acid is required for brain and skeletal development.

PMID27213289

Indication: Metabolic (N-Acetylneuraminic Acid Storage Disease; OMIM #605202)

Clinical Trial: NCT03545568

Drug: Sialic acid

Zebrafish Screening Assay: Rescue of the abnormal skeletal development in zebrafiish knockdown of NANS (the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid))

Reported observations: In zebrafish embryos, exogenously added sialic acid was able to partially rescue the developmental phenotype caused by NANS knockdown.

Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models

PMC3148081

Indication: Leukaemia, graft versus host disease (GvHD)

Clinical Trial: Phase II; NCT01627314, NCT00890500

Drug: ProHema (PGE2 derivative)

Zebrafish Screening Assay: HSC expansion in development Leukaemia, graft versus host

Reported observations: dmPGE2 mediates conserved responses in Hematopoietic stem cells (HSCs) from human and nonhuman primates and provided sufficient preclinical information to support proceeding to an FDA-approved phase 1 clinical trial.

Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma

PMC6170170

Indication: Adenoid cystic carcinoma

Clinical Trial: Phase II; NCT03999684

Drug: All- trans retinoic acid

Zebrafish Screening Assay: Pluripotent zebrafish blastomere culture

Reported observations: Our findings establish the zebrafish pluripotent cell culture system as a method to identify modulators of tumor formation, particularly establishing retinoic acid as a potential new effective therapy for ACC.

DHODH modulates transcriptional elongation in the neural crest and melanoma

PMC3759979

Indication: Melanoma

Clinical Trial: Phase I (on hold); NCT01611675

Drug: Leflunomide

Zebrafish Screening Assay: Inhibit neural crest development

Reported observations: One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

PMC5873857

Indication: Arteriovenous malformation

Clinical Trial: Compassionate use, planned clinical trials

Drug: MAPK pathway inhibitors

Zebrafish Screening Assay: Rescue blood flow in BRAF- mutant transgenic model

Reported observations: Our findings in transgenic zebrafish uncover a major cause of sporadic vascular malformations (VMs) of different clinical types: multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1. Thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

PMID: 31263281

Indication: Lymphatic disease

Clinical Trial: Compassionate use

Drug: MEK Inhibitor

Zebrafish Screening Assay: Prevent lymphatic disease in ARAF- mutant transgenic model

Reported observations: The functional relevance of the ARAF-S214P mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement.

BMP type I receptor inhibition reduces heterotopic [corrected] ossification

PMC2846458

Indication: Fibrodysplasia ossificans progressiva; iron deficiency anaemia; iron- refractory iron deficiency anaemia

Clinical Trial: Phase I; ACTRN12619000319178

Drug: KER-047: ALK2 inhibitors (dorsomorphin derivatives)

Zebrafish Screening Assay: Dorsalization of developing embryo

Reported observations: These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of Fibrodysplasia ossificans progressiva (FOP) and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

PMC3904599

Indication: T cell acute lymphoblastic leukaemia

Clinical Trial: Preclinical

Drug: Perphenazine and derivativesa (PP2A activator)

Zebrafish Screening Assay: Selective toxicity for
MYC-overexpressing thymocytes

Reported observations: Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T cell acute lymphoblastic leukemia (T-ALL) and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.