MORBIUS · Cure for Miniature Brittle Bones: Treatment of Osteogenesis ImpeRfecta patient-derived Bone organoids with Innovative AAV-mediated Ultimate Gene-editing System

Osteogenesis Imperfecta (OI), also known as brittle bone disease, is a prevalent rare skeletal condition. With limited treatment options available and no known cure, individuals with OI endure numerous bone fractures throughout their lives. To address the urgent need for an OI cure, MORBIUS aims to create a gene therapy: employ a cutting-edge AAV-mediated gene editing, to curatively repair the genetic defect in a model of patient bone tissue (mini brittle bone). Within MORBIUS I will: 1) construct mini brittle bones - an OI patient-derived induced stem cell-based bone organoid system, and 2) repair the genetic defect in the mini brittle bones with the AAV-based CRISPR/Cas and GeneRide strategy. To this end, with access to one of the largest OI cell line biobanks in the world, I will combine highly innovative induced stem cell development techniques with the existing expertise in fabrication of bone organoids of the hosting team and genome modification competence of secondment host.Specifically, I will optimize a method of OI patient-derived induced mesenchymal stem cells embedding in a decellularized extracellular matrix to promote their natural differentiation and formation of mini brittle bones. Crafted mini brittle bones will be transduced with bone-directed AAV vector carrying CRISPR/Cas and GeneRide systems to correct patients genetic defect by targeted insertion of a donor sequence.In synergy with gene therapy research, during a non-academic placement with an OI patient organization, an interactive multilingual educational webapp on OI gene therapy and genetics will be developed. This will ensure early knowledge sharing, awareness, building of trust, and encouragement of OI individuals to actively engage in gene therapy advancements. MORBIUS outcomes will enhance the quality of life for individuals with OI and other rare bone disorders, but introduction of effective gene editing, bone organoid modeling, and knowledge sharing methods.