Frontiers in Endocrinology (Sep 2024)

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

  • Sara Penna,
  • Alessandra Zecchillo,
  • Alessandra Zecchillo,
  • Martina Di Verniere,
  • Elena Fontana,
  • Elena Fontana,
  • Valeria Iannello,
  • Valeria Iannello,
  • Eleonora Palagano,
  • Eleonora Palagano,
  • Stefano Mantero,
  • Stefano Mantero,
  • Andrea Cappelleri,
  • Andrea Cappelleri,
  • Elena Rizzoli,
  • Elena Rizzoli,
  • Ludovica Santi,
  • Laura Crisafulli,
  • Laura Crisafulli,
  • Marta Filibian,
  • Antonella Forlino,
  • Luca Basso-Ricci,
  • Serena Scala,
  • Eugenio Scanziani,
  • Eugenio Scanziani,
  • Thorsten Schinke,
  • Francesca Ficara,
  • Francesca Ficara,
  • Cristina Sobacchi,
  • Cristina Sobacchi,
  • Anna Villa,
  • Anna Villa,
  • Valentina Capo,
  • Valentina Capo

DOI
https://doi.org/10.3389/fendo.2024.1450349
Journal volume & issue
Vol. 15

Abstract

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IntroductionAutosomal 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.MethodsThe 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.ResultsFirst, 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.ConclusionThese 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.

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