In-depth phenotyping and experimental therapy of autosomal dominant osteopetrosis

In this study, we aim at investigating the mechanisms that induce a form of osteopetrosis generally observed in adolescents and adults, denominated Autosomal Dominant Osteopetrosis type 2 (ADO2). We will exploit mouse models of this disease that have been generated in our laboratory. We want to understand the cellular mechanisms disrupted in ADO2 and ascertain if bone is the only organ affected. We have evidence that ADO2 mice show signs of motor/behavioural failures and the involved gene, called clcn7, is highly expressed in many organs where its pathogenetic relevance in ADO2 is still unknown. Using our mouse models we will understand whether and how other organs are affected by a specific clcn7 mutation (p.G213R), allowing a comprehensive analysis of the ADO2 phenotype. We have previously worked on a new therapy and provided the proof of principle that we can strongly reduce the expression of the disease gene through treatment with molecules called siRNAs, without harming the normal gene. Now that the ADO2 mice are available, we can translate this knowledge into an experimental therapy and set up treatment protocols that could impact future therapies in humans. From this study we expect to i) identify the cellular mechanisms disrupted in p.G213R-clcn7 dependent ADO2, ii) recognise the pathogenetic role of our clcn7 ADO2 mutation not only in bone but also in other organs, and iii) establish protocols for an experimental therapy of ADO2 that may help future developments to treat patients.