Development of Gene Therapy for Malignant Osteopetrosis
Osteoclasts and osteoblasts are two important mediators in the tightly regulated process of bone remodelling. The bone-forming osteoblasts are of mesenchymal origin while the multinucleate osteoclasts, which are responsible for bone resorption, are derived from hematopoietic stem cells (HSCs). An imbalance between the production and destruction of bone can lead to either reduction (osteoporosis) or increase (osteopetrosis) of bone mass.
Osteopetrosis comprises a heterogeneous group of diseases with varying degree of osteoclast dysfunction. The most severe form is called infantile malignant osteopetrosis, IMO. Children with this rare disorder have normal or elevated numbers of osteoclasts, which are unable to resorb bone due to defects in the acidification of the subcellular space between the osteoclast and the bone surface.
The gene mutated in the majority of IMO patients is called TCIRG1. Its transcript codes for a subunit of a proton pump that osteoclasts use to acidify the resorption area. Mutations in TCIRG1 cause a lack of resorption and hence severely hamper bone remodelling, which results in dense and fragile bones. This in turn causes bone marrow failure followed by anemia and hepatosplenomegaly.
The only curative treatment for IMO is hematopoietic stem cell transplantation. IMO is a candidate disease for development of gene therapy because of its fatal outcome early in life if treatment with HSC transplantation is not available. Experience from gene therapy studies of other diseases with hematopoietic involvement, such as X-linked SCID and chronic granulomatous disease, show promising results. Gene therapy of IMO has so far not been performed in patients with IMO.
- To develop hematopoietic stem cell based gene therapy of infantile malignant osteopetrosis (IMO)
- To increase our knowledge about osteoclasts and their function in bone turnover and hematopoiesis
The main objective of our research is to develop hematopoietic stem cell based gene therapy protocols that aim at curing IMO patients.
(name linked to profile in Lund University research portal)
Principal investigator, Professor, Johan [dot] Richter [at] med [dot] lu [dot] se
Staff Scientist, Ilana [dot] Moscatelli [at] med [dot] lu [dot] se