Development of Gene Therapy for Malignant Osteopetrosis

Group members: Maria Johansson, Carmen Flores and Johan Richter

Aims of the project

• Specific aim: Develop hematopoietic stem cell based gene therapy of infantile malignant osteopetrosis (IMO)
• General aim: Increase our knowledge about osteoclasts and their function.

Osteopetrosis and osteoclasts

The osteoclast and the osteoblast are two important mediators in the tightly regulated process of bone remodeling. The bone-forming osteoblasts are of mesenchymal origin while the multinucleated osteoclasts that are responsible for bone resorption, are derived from hematopoietic stem cells, HSCs (Fig 1). The balance between production and destruction of bone can be disturbed, and this will result in either reduction (osteoporosis) or increase (osteopetrosis) of bone mass.

Figure 1: Osteopetrosis comprises a heterogeneous group of diseases with varying degree of osteoclast dysfunction and the most severe form is 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 (Fig 2).

Figure 2:The gene mutated in the majority of patients with IMO is called TCIRG1 (or ATP6I or OC116 ). The 2,7 kbp transcript codes for the a 3 subunit of a proton pump used by the osteoclast to acidify the resorption area. As a consequence of the lack of resorption, remodeling of bone is severely hampered, which results in dense and fragile bone. This in turn causes bone marrow (BM) failure followed by anemia and hepatosplenomegaly.

The only curative treatment for IMO is HSC 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 tested in animal models or in patients. We have previously demonstrated that a mouse model of IMO, the oc/oc mouse, which has a deletion in the tcirg1 gene, can be treated with neonatal BM transplantation (1). Based on these results we have now also developed neonatal hematopoietic stem cell targeted gene therapy in this mouse model of the disease using a retroviral vector expressing the tcirg1 gene (2). Ongoing work will focus on the human form of the disease.

Selected Recent and Key Publications

1. M . Johansson, L. Jansson, M. Ehinger, A. Fasth, S. Karlsson and J. Richter. Neonatal hematopoietic stem cell transplantation cures oc/oc mice from osteopetrosis. 2006. Exp. Hematol. 34(2):242-9.
2. M . Johansson, T. J. de Vries, M. Ehinger, A. Fasth, S. Karlsson. V. Everts and J. Richter. Hematopoietic stem cell targeted neonatal gene therapy cures oc/oc mice from osteopetrosis. Abstract to ISEH and ASH meetings 2006

Collaborators:

• Mats Ehinger, Department of Pathology, Lund University , Lund , Sweden.
• Anders Fasth, Department of Pediatrics, Göteborg University , Gothenburg , Sweden.
• Vincent Everts, T eun J. de Vries and Ton Schoenmaker, Department of Periodontology and Oral Cell Biology, Academic Center for Dentistry Amsterdam Universiteit van Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands.
• Oscar Porras, Hospital Nacional des Niños, San José , Costa Rica.

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