Autosomal Dominant Osteopetrosis Type 2 (ADO2): close to the cure. What do we miss?

The aim of this project is to advance an innovative therapy for ADO2 that uses a molecule called siRNA, proven to be effective and safe in mice affected by the disease. This therapy targets a gene called CLCN7 only in its diseased form, thus preventing its altered function. In contrast, it does not affect the function of the normal gene, thus rescuing the normality because in ADO2 only one of the two genes of the couple is altered. The aim of this project is to progress the therapy towards the clinic, and to do so we must fill some gaps related to the formulation of our siRNA as a medicine. This step is mandatory to gain the authorization to perform early phases clinical studies. To achieve this goal, we must optimize the siRNA delivery. For this reason we will design various formulations of the siRNA and will investigate which of these potential medicines will show the best performance and the easiest way to be administered. To do so, we will first shortlist a variety of formulations by studies in cells, then we will test them in mice affected by ADO2. Finally, we will select a few potential medicinal products on which, beyond this project, we will perform studies of toxicity to select the one for which we will request the authorization to the drug agencies to perform the first experiments on a small group of patients. When the medicinal product will be identified and proven effective and safe, we will be in the position to move it to the clinic, which is the final long-term goal of our project. Should this process be successful, this would be the very first targeted therapy for a disease with high morbidity and no cure.