A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA)
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.
Authors
- Jason Otterstrom (ORCID: https://orcid.org/0000-0002-0176-9976)
- Ivan Bassi (ORCID: https://orcid.org/0000-0002-9921-2083)
- Camila Avivi (ORCID: https://orcid.org/0000-0002-8238-8277)
- Yael Paran (ORCID: https://orcid.org/0000-0001-9544-6213)
- Noga Moshe
- Yaara Tevet
- Giuseppina Lambiase (ORCID: https://orcid.org/0000-0001-6424-9065)
- Polina Geva (ORCID: https://orcid.org/0000-0002-8782-2781)
- Haim Michael Barr (ORCID: https://orcid.org/0000-0001-9192-3983)
- Gil S. Leichner
- A Barzilai (ORCID: https://orcid.org/0000-0003-1730-6383)
- Lotan Levin (ORCID: https://orcid.org/0000-0002-5380-8463)
- Shoshana Greenberger (ORCID: https://orcid.org/0000-0001-8308-2790)
- Gal Perlmoter (ORCID: https://orcid.org/0000-0003-2017-3008)
- Karina Yaniv (ORCID: https://orcid.org/0000-0001-5638-7150)
- Naama Farag (ORCID: https://orcid.org/0009-0003-1794-9749)
- Shany Egozi (ORCID: https://orcid.org/0009-0003-1700-9589)
- Amani Jabali (ORCID: https://orcid.org/0009-0007-7393-8787)
- Jonathan Long (ORCID: https://orcid.org/0009-0001-0850-7864)
Institutions
- Tel Aviv University (IL)
- Sheba Medical Center (IL)
- American Committee for the Weizmann Institute of Science (US)
- IDEA Bio-Medical (Israel) (IL)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-08-21
- DOI
- https://doi.org/10.1084/jem.20240513
- Citations
- 1
- Primary Topic
- CNS Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- Weizmann Institute of Science
- European Research Council
- Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania