A pharmacological approach to RANKL-dependent osteoclast-poor Autosomal Recessive Osteopetrosis

"Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts, the cells responsible for this activity. Among them, infantile malignant, autosomal recessive osteopetrosis (ARO) presents soon after birth and is often lethal in early life. To date, the only therapy is hemopoietic stem cells transplantation (HSCT), which is more likely to be successful when a compatible donor is available. Our recent results have shown that, even when it restores the hematological compartment, the HSCT approach has no possibility to cure the bone disease in patients bearing mutations in RANKL gene, because in these cases the defect is intrinsic to the osteoblasts, which are cells of mesenchymal, not hemopoietic, origin. Our project aims to: 1) verify the effects of the pharmacological administration of soluble RANKL in the mouse model trance-/-. We will assess whether such therapy could rescue the bone defect and determine the effects on the immune system, which is altered in the trance-/- mouse, and on other organs potentially affected. 2) To verify the acute and chronic toxicity of the proposed pharmacological approach, in order to evaluate its safety; 3) to start the production of clinical grade RANKL, in order to perform a clinical trial with the administration of the cytokine to the RANKL-dependent patients already identified. At the same time, we aim to select new RANKL-dependent cases among the ARO patients that will be referred to our centre, in order to involve them, too, in our clinical protocol. Our research will allow us to precisely diagnose individuals affected by osteopetrosis; the studies performed on trance-/- mice will give suggestions on the pros and cons of a pharmacological approach with recombinant RANKL in RANKL-deficient ARO and allow us to define a protocol for a clinical trial, which we will perform thanks to the collaboration of a specialised centre in the UK (Dr. M.Abinun, Newcastle General Hospital).