Zebrafish drug screen finds no rescue for Marfan syndrome heart stress

Marfan syndrome is a life-threatening inherited connective tissue disorder caused by pathogenic variants in the fibrillin-1 gene, and it is characterized by progressive cardiovascular disease. Current medical therapies can slow disease progression, but they do not prevent major complications, which underscores the need for new treatment strategies and unbiased approaches to drug discovery. A new study in BMC Pharmacology and Toxicology describes an integrated zebrafish-based platform built to meet that need, combining quantitative molecular readouts with detailed phenotypic profiling in a living vertebrate model.

The researchers worked with a zebrafish model of Marfan syndrome that lacks fibrillin-3, a model that recapitulates key cardiovascular features of the human disease, including cardiac stress, valvular defects, arrhythmia, and aortic dilation. To measure cardiac stress sensitively and quantitatively, the team generated a novel transgenic reporter zebrafish expressing secreted nanoluciferase under the control of the stress-responsive nppb promoter.

The reporter performed strongly in validation experiments. Larvae lacking fibrillin-3 showed markedly elevated nppb activity that correlated with phenotypic severity and peaked during developmental stages of highest mortality, indicating that the molecular signal tracks closely with the visible and lethal manifestations of disease. The nanoluciferase assay offered a dynamic range of roughly 1,000-fold, substantially outperforming assays based on Firefly luciferase, which makes it a sensitive tool for detecting changes in cardiovascular stress in high-throughput settings.

Using this platform, the team evaluated existing and candidate therapies for Marfan syndrome. Pharmacological inhibition of TGF-β signaling, a pathway long implicated in the condition, produced only transient or deleterious effects, highlighting the context-dependent nature of modulating this pathway. Standard treatments also fell short: β-blockers, the angiotensin receptor blocker losartan, and allopurinol failed to consistently improve cardiac stress, pericardial edema, or dilation of the bulbus arteriosus in the model.

The centerpiece of the study was an unbiased high-throughput drug screen of more than 1,500 clinically approved compounds, tested across multiple developmental treatment windows. The screen identified a small number of primary and secondary hits, compounds that initially appeared to reduce disease readouts. However, none of these candidates demonstrated reproducible phenotypic rescue when subjected to rigorous validation involving multiple doses and multiple treatment windows. In other words, no definitive therapeutic candidate emerged from the screen.

The authors conclude that the study establishes a sensitive zebrafish-based platform for early, quantitative assessment of cardiovascular stress in Marfan syndrome, while also highlighting the limited efficacy of current therapies, the context-dependent effects of TGF-β modulation, and the biological complexity underlying the disease. Although the search for disease-modifying interventions did not yield a winning compound, the work lays a foundation for expanded unbiased discovery efforts, and the open-access study was published on 29 October 2026.

Subject of Research: A zebrafish nanoluciferase reporter platform for quantitative drug discovery in Marfan syndrome

Article Title: Integrated luminescence and phenotypic profiling for drug discovery in a zebrafish model of Marfan syndrome

Article References: Horvat, M., Caboor, L., De Rycke, K., Mennens, L., Daniels, E., Wyseur, J., Verhelst, E., Roos, I., Rodríguez-Rovira, I., Egea, G., De Backer, J., & Sips, P. (2026). Integrated luminescence and phenotypic profiling for drug discovery in a zebrafish model of Marfan syndrome. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01271-4

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01271-4

Keywords: Marfan syndrome, zebrafish, nanoluciferase, drug screening, TGF-β signaling, fibrillin-3, cardiovascular disease, aortic dilation, nppb promoter, losartan, beta-blockers, high-throughput screening