ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia
Qutaina, S.; Zhao, H.; Wang, Z.; Sullivan, A.; Geddie, M.; Kaur, R.; Tian, H.; Yue, H.; Wang, X.; Guo, S.; Bruni, M.; Christen, E.; Campagne, F.; Arthur, H. M.; Andre, P.; Marambaud, P.
Show abstract
Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations (AVMs) and severe bleeding caused by loss-of-function mutations in the ALK1 receptor pathway. We developed clustering agonist bispecific antibodies (BsAbs) targeting ALK1 and its activating partner, the Ser/Thr receptor kinase BMPRII. These BsAbs induced ALK1-BMPRII proximity association, stimulated the downstream Smad1/5/8 signaling cascade, and treated HHT pathologies in various mouse models. BsAb treatment reduced AVM burden by up to 95% in HHT mice, preventing anemia, cardiomegaly, and premature death. The BsAbs also enhanced Smad1/5/8 signaling in endothelial cells derived from HHT patients with ALK1 mutations and prevented retinal AVMs in a newly developed knock-in mouse carrying an HHT-causing ALK1 mutation. These findings establish ALK1-BMPRII agonism as a promising therapeutic strategy for HHT.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma 96%
- ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1 94%
- Multiomic Profiling Reveals Metabolic Alterations Mediating Aberrant Platelet Activity and Inflammation in Myeloproliferative Neoplasms 93%
Similar papers in this journal
Similar papers in this journal
- C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function 94%
- Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer 94%
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology 93%
Similar papers in this journal
- Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages 94%
- Single-cell analysis reveals distinct fibroblast plasticity during tenocyte regeneration in zebrafish 94%
- Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine. 94%
Similar papers in this journal
- TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques 94%
- Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size 93%
- Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.