Lentiviral-mediated gene transfer of TCIRG1 to correct osteoclast function in autosomal recessive osteopetrosis: a pilot study

Autosomal recessive osteopetrosis (ARO) is a rare, fatal genetic disease. The main pathological features are present at birth and are characterized by general osteosclerosis, increased susceptibility to fractures, facial nerves entrapment and hydrocephalus due to failure of skull base remodeling. Hematopoietic stem cell transplantation (HSCT) is the only therapeutic option (Coccia et al., 1980), however allogeneic transplantation remains a challenge and indicates the urgent need to improve engraftment by developing novel strategies that can allow the transplant of autologous gene corrected hematopoietic cells able to reconstitute the hematopoietic system. In this project, we will develop a gene therapy platform to offer as alternative cure to HSCT, exploiting circulating hematopoietic stem and progenitor cells (HSPCs). Patient CD34+ cells will be corrected with clinically optimized lentiviral vector and expanded, to limit the needed amount of blood. We aim to study the functionality and subset distribution of circulating HSPCs, which have never been elucidated. We will use humanized mouse models to assess the capacity of corrected and expanded cells to provide life-long supply of hematopoietic cells of different lineages. Finally, we will test novel non-genotoxic conditioning regimens, to reduce transplant-related complications and toxicities. These improvements will allow safer treatment of severely affected newborns with ARO and other diseases