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Correction of haematopoietic stem cells from Bernard-Soulier syndrome patients and disease models by gene therapy

G Martinez-Navajas(1,2) J Ceron-Hernandez(1,2) I Simon-Saez(2) J M Sanchez-Mañas(2) F Martin(2) J Rivera(3) P J Real(1,2)

1:University of Granada; 2:GENYO. Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government; 3:Department of Haematology and Medical Oncology, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, 30008 Murcia, Spain.

Platelets recognize injured vascular vessels by the interaction between GPIB-V-IX platelet receptor and von Willebrand factor (VWF), contained in the exposed subendothelial matrix of the damaged area. The absence of this receptor impedes proper plug formation because platelets cannot recognize damaged vessels. This is the origin of an extremely rare disease denominated Bernard-Soulier Syndrome (BSS). Mutations of GPIB-V-IX receptor genes avoid its migration to the membrane and consequently clot formation.

Last decades, several gene therapy approaches for hematologic diseases have been successfully carried out. Our lab has developed a novel treatment for BSS subtype C based on the use of Lentiviral Vectors (LVs) to revert the disease originated by GP9 mutations. 

Firstly, we have reverted the disease phenotype on a GP9-Knock-out megakaryoblastic cell line (DAMI), which regularly expresses the GPIB-V-IX complex on its surface. Secondly, we have rescued a BSS model based on iPSCs from BSS patients. This model allows us to analyze our LVs behaviour along a differentiation process. Finally, we have isolated Hematopoietic Stem Cells from BSS peripheral blood samples and treated them with our LVs. The reappearance of the complex after a differentiation towards megakaryocytic lineage indicates the reversal of BSS in vitro. All together our results demonstrated that we can revert GPIX expression on human BSS models. 

Next, we will complete rescue experiments in a GP9-knock-out BSS animal model. We consider that all these results will allow us to propose an ex vivo curative LV-based gene therapy on Hematopoietic Stem Cells from BSS patients.

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