@misc{10481/99837,
year = {2023},
month = {6},
url = {https://hdl.handle.net/10481/99837},
abstract = {Bernard-Soulier syndrome (BSS) is a rare congenital disease characterized by macrothrombocytopenia and frequent bleeding. It is caused by pathogenic variants in three genes (GP1BA, GP1BB, or GP9) that encode for the GPIbα, GPIbβ, and GPIX subunits of the GPIb-V-IX complex, the main platelet surface receptor for von Willebrand factor, being essential for platelet adhesion and aggregation. According to the affected gene, we distinguish BSS type A1 (GP1BA), type B (GP1BB), or type C (GP9). Pathogenic variants in these genes cause absent, incomplete, or dysfunctional GPIb-V-IX receptor and, consequently, a hemorrhagic phenotype. Using gene-editing tools, we generated knockout (KO) human cellular models that helped us to better understand GPIb-V-IX complex assembly. Furthermore, we developed novel lentiviral vectors capable of correcting GPIX expression, localization, and functionality in human GP9-KO megakaryoblastic cell lines. Generated GP9-KO induced pluripotent stem cells produced platelets that recapitulated the BSS phenotype: absence of GPIX on the membrane surface and large size. Importantly, gene therapy tools reverted both characteristics. Finally, hematopoietic stem cells from two unrelated BSS type C patients were transduced with the gene therapy vectors and differentiated to produce GPIX-expressing megakaryocytes and platelets with a reduced size. These results demonstrate the potential of lentiviral-based gene therapy to rescue BSS type C.},
organization = {Grupo de Regulación Génica, Células Madre y Desarrollo},
keywords = {RNA/DNA editing},
keywords = {Bernard-Soulier Syndrome},
keywords = {Gene therapy},
keywords = {GP9},
keywords = {Hematopoietic stem cells},
keywords = {Disease models},
keywords = {Induced pluripotent stem cells},
keywords = {Lentiviral vector},
keywords = {CRISPR-Cas9},
keywords = {GPIb-V-IX receptor},
keywords = {von Willebrand factor},
keywords = {Edición génica},
keywords = {Síndrome de Bernard-Soulier},
keywords = {Terapia génica},
keywords = {Células madre hematopoyéticas},
keywords = {Modelos de enfermedad},
keywords = {Células madre pluripotentes},
keywords = {Vector lentiviral},
title = {Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C},
doi = {10.1016/j.omtn.2023.06.008},
author = {Martínez Navajas, Gonzalo and Ceron-Hernandez, Jorge and Simon, Iris and Lupiañez, Pablo and Diaz-McLynn, Sofia and Perales, Sonia and Modlich, Ute and Guerrero, José Antonio and Martin, Francisco and Sevivas, Teresa and Lozano, María Luisa and Rivera, Jose and Ramos Mejía, Verónica and Tersteeg, Claudia and Real Luna, Pedro José},
}