PORTEFEUILLE

Lymphedema-distichiasis is a rare hereditary disease characterized by swelling of the legs because of abnormal interstitial fluid transport (lymphedema) and the presence of additional set of eyelashes (distichiasis). Additional defects may include cleft palate and heart malformations. While distichiasis can usually be successfully treated, at present no cure exists for lymphedema, which is a highly disabling and disfiguring condition.

Lymphedema-distichiasis is caused by loss-of-function mutations in the transcription factor FOXC2. We have recently established inducible loss- and gain-of-functions genetic models to study the pathology of lymphedema-distichiasis, and we identified FOXC2 target genes in lymphatic vessels, tissues that are most affected in individuals with this disease. The goal of this project is to evaluate theurapeutic potential of some of these genes to prevent or improve lymphedema caused by the FOXC2 deficiency. We plan to address these questions through the analysis of mice with lymphatic endothelial specific deletion of FOXC2 targets, as well as by studying the ability of recombinant proteins or small molecule inhibitors to prevent the development of lymphedema in our preclinical models.

Lymphedema is a chronic condition for which no effective cure exists at the moment. Due to the progress of both clinical and fundamental research, we now understand that multiple causes underlie the pathology of this disease. Mutations in FOXC2 cause human hereditary lymphedema-distichiasis. In our work we propose to combine basic knowledge derived from the studies of molecular biology of FOXC2 and results from genetic models to develop a rational approach for targeting the defects of lymphatic vasculature. Although lymphedema-distichiasis is a rare diseases, we hope that new knowledge and methods developed during our work will be useful for treatment of other diseases, in which lymphatic vessels play an important role, such as cancer and inflammation.

The project developed a useful pre-clinical model of lymphedema-distichiasis and identified signaling pathway and down-stream effectors of FOXC2. Surpisingly, we found that FOXC2 regulates mechanosensitive responses of lymphatic endothelial cells, demonstrating that lymphedema-distichiasis is a disease of impaired mechanotransduction (Sabine et al., in revision). We also explored a potential of cancer drug repurposing, and identified potentially interesting candidates, which we are currently testing in our new model. We hope that the results of these experiments will allow to initiate mechanism-based clinical trials, and, ultimately, improve the outcome of the disease in human patients.

21.9.15: The Journal of Cilinical Investigation: FOX2 and fluid shear stress stabilize postnatal lymphatic vasculature http://www.jci.org/articles/view/80454