NEW THERAPEUTIC APPROACHES TO OSTEOPETROSIS

Osteopetrosis is a genetic bone disease often resulting in severe morbidity and very early death. It is due to the defective function of cells, called osteoclasts, which normally resorb bone matrix, thus allowing its replacement with high-quality new bone and ensuring skeleton homeostasis. Osteoclast failure causes persistence of old bone, increase of bone density and obstruction of the internal cavities containing vital organs such as the bone marrow and the nervous system. Short stature, deformities and pathological fractures are typical symptoms, along with severe haematological and neural failures. Currently, no efficacious pharmacological cure is available. The malignant forms are treated with bone marrow transplantation. However, long-term survival is observed in less than 50% of transplanted patients, who remain short and often present with persistence of neural damages, including vision deterioration. In this proposal we aim at studying innovative treatments to be tested in cell and animal models. For the malignant forms we intend to develop a method for providing patients with readily available sources of committed osteoclast precursors to be injected for cell therapy. These cells could provide immediate bone resorption and improve the outcome of bone marrow transplantation or suffice for an improvement in those patients who cannot be transplanted or who experienced transplant failure. Approximately 70% of patients with the less severe forms harbour a single allele mutation of a gene called CLCN7. We intend to eliminate this mutant allele using a new technology, termed RNA interference. We hypothesise this method will rescue a condition similar to that of unaffected carriers, who are phenotypically normal. We expect these approaches provide first hand information on the feasibility of innovative therapies to prevent the severe symptoms of the disease.