Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

TY - JOUR

T1 - Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

AU - Penna, Sara

AU - Zecchillo, Alessandra

AU - Di Verniere, Martina

AU - Fontana, Elena

AU - Iannello, Valeria

AU - Palagano, Eleonora

AU - Mantero, Stefano

AU - Cappelleri, Andrea

AU - Rizzoli, Elena

AU - Santi, Ludovica

AU - Crisafulli, Laura

AU - Filibian, Marta

AU - Forlino, Antonella

AU - Basso-Ricci, Luca

AU - Scala, Serena

AU - Scanziani, Eugenio

AU - Schinke, Thorsten

AU - Ficara, Francesca

AU - Sobacchi, Cristina

AU - Villa, Anna

AU - Capo, Valentina

N1 - Copyright © 2024 Penna, Zecchillo, Di Verniere, Fontana, Iannello, Palagano, Mantero, Cappelleri, Rizzoli, Santi, Crisafulli, Filibian, Forlino, Basso-Ricci, Scala, Scanziani, Schinke, Ficara, Sobacchi, Villa and Capo.

PY - 2024

Y1 - 2024

N2 - INTRODUCTION: Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. METHODS: The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. RESULTS: First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity.CONCLUSION: These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.

AB - INTRODUCTION: Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. METHODS: The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. RESULTS: First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity.CONCLUSION: These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.

U2 - 10.3389/fendo.2024.1450349

DO - 10.3389/fendo.2024.1450349

M3 - SCORING: Journal article

C2 - 39314524

VL - 15

SP - 1450349

JO - FRONT ENDOCRINOL

JF - FRONT ENDOCRINOL

SN - 1664-2392

ER -