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Published on: April 10, 2020
A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA)
Ivan Bassi1, Amani Jabali2,3, Lotan Levin3
1Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Kaposiform lymphangiomatosis (KLA) is a rare and aggressive disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by conditionally expressing the human NRAS mutation in venous and lymphatic ECs. Mutant embryos recapitulate key clinical features of KLA, including dilated lymphatics and pericardial edema, which are reversed by trametinib, a MEK inhibitor used in KLA treatment. Leveraging this model in combination with an AI-based high-throughput drug screening platform, we identify cabozantinib, a tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as promising candidates for treating KLA. Notably, both drugs normalized sprouting and migration of cultured LECs from a KLA patient. Overall, our novel zebrafish model provides a powerful platform to dissect KLA pathogenesis and identify new therapeutic avenues.
Insights
A new zebrafish model accurately mimics Kaposiform lymphangiomatosis (KLA), a rare vascular disorder. This model aids in identifying new KLA treatments, including cabozantinib and GSK690693, offering hope for patients.
Area of Science:
- Vascular biology
- Zebrafish disease modeling
- Oncology
Background:
- Kaposiform lymphangiomatosis (KLA) is an aggressive vascular anomaly driven by NRAS mutations.
- Current therapeutic strategies are limited by a lack of faithful preclinical models.
- Understanding KLA pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To establish a novel zebrafish model for Kaposiform lymphangiomatosis.
- To utilize the model for high-throughput drug screening.
- To identify novel therapeutic agents for KLA treatment.
Main Methods:
- Conditional expression of human NRAS (p.Q61R) in zebrafish lymphatic and venous endothelial cells.
- Phenotypic analysis of KLA-like features in mutant zebrafish embryos.
- AI-based high-throughput drug screening and in vitro validation.
Main Results:
- The zebrafish model recapitulates key KLA clinical features, including lymphatic dilation and edema.
- Trametinib, a MEK inhibitor, reversed KLA phenotypes in the zebrafish model.
- Cabozantinib and GSK690693 were identified as promising KLA therapeutics, normalizing patient-derived LECs.
Conclusions:
- A novel zebrafish model effectively replicates KLA, offering a platform for disease mechanism studies.
- The identified drugs, cabozantinib and GSK690693, show therapeutic potential for KLA.
- This research paves the way for accelerated discovery of KLA treatments.
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