Abstract PROOF

This proposal aims to repurpose RAVICTI, an FDA-approved ammonia scavenger for Urea Cycle Disorder (UCD), as a potential chaperone therapy for osteogenesis imperfecta (OI), a rare genetic disorder causing extreme bone fragility due to collagen I defects. Currently, no drug specifically designed for OI is available worldwide, except for bisphosphonates in Italy and Japan. However, these primarily function by reducing bone resorption rather than directly enhancing cellular homeostasis and bone properties. Emerging evidence from literature and preliminary data from Consortium members suggests that endoplasmic reticulum (ER) stress, resulting from the intracellular retention of mutant collagen, contributes significantly to OI severity. The active pharmacological ingredient in RAVICTI, 4-phenylbutyrate, has shown promise in rescuing cellular homeostasis and promoting collagen I secretion in OI models. Our study will leverage both in vivo and in vitro approaches, using OI murine models and advanced 2D and 3D human cell cultures to assess the impact of RAVICTI on bone properties and unravel its cellular mechanisms. High resolution imaging techniques and OMICS approaches will be used and the results from basic science models will provide a broad overview of RAVICTI effect at macro and cellular levels. Led by a multidisciplinary team of experts in OI, the project ensures a rapid transition from preclinical findings to Phase 2 clinical trial. With the support from the pharmaceutical company producing RAVICTI and from the EU-funded Remedi4All initiative and MetabERN, dealing with UCD patient cohorts, the project also benefits from direct engagement with EU umbrella OI PAO from study design through clinical trial preparation to maintain a patient-centered approach. This collaborative effort will accelerate the repurposing of RAVICTI for OI, maximizing its potential impact.