nintedanib has been researched along with Telangiectasia--Hereditary-Hemorrhagic* in 2 studies
2 other study(ies) available for nintedanib and Telangiectasia--Hereditary-Hemorrhagic
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Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models.
Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT. Topics: Activin Receptors, Type II; Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Endothelial Cells; Growth Differentiation Factor 2; Indoles; Mice; Mice, Knockout; Signal Transduction; Sirolimus; Smad1 Protein; Smad5 Protein; Smad8 Protein; Telangiectasia, Hereditary Hemorrhagic; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor Receptor-2 | 2020 |
Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia.
A 70-year-old patient with known hereditary haemorrhagictelangiectasia (HHT) was seen regularly in our outpatient clinic. He underwent multiple therapeutical interventions, including both surgical and medical, for the treatment of recurrent epistaxis without sustained success. Due to a concurrent diagnosis of idiopathic pulmonary fibrosis, treatment with the tyrosine kinase inhibitor nintedanib was initiated, after which point the patient reported a dramatic and unanticipated improvement in his epistaxis and skin telangiectasia. On the basis of this case report, we propose that nintedanib may be a potential treatment option for refractory epistaxis in HHT. Topics: Aged; Enzyme Inhibitors; Epistaxis; Humans; Indoles; Male; Protein-Tyrosine Kinases; Pulmonary Fibrosis; Skin Diseases; Telangiectasia, Hereditary Hemorrhagic | 2017 |