Musculoskeletal disease is the most common cause of disability and loss of independency in the ageing populations across the globe. In this context, bone fractures and their complete healing also plays an important role. Due to the intrinsic regenerative capability of bone, in many cases, fractures can heal in a fast and effective way. However, healing of 10-15% of fractures is impaired leading to non-unions (failure of fracture healing after 6 months). Treatment of non-unions for patients comorbid with metabolic abnormalities such as type 2 diabetes mellitus (T2DM) is particularly difficult, and remains an unresolved clinical challenge. Within SyMBoD - a consortium of five academic partners and Genevention, funded by the BMBF - specialists congregated aiming at the provision of optimized and individualized diagnosis and therapy options promoting endogenous regeneration in this field of unsolved clinical need by the development of an innovative system medicine-based digital technology towards a theranostic platform. Patients with non-union and type 2 diabetes mellitus (T2DM) will serve as a role model to achieve a holistic understanding of system interplay that would impede regeneration and lead to substantial morbidity. In the second phase of the project, patients with a lack of endogenous bone regeneration capability (diagnostics based on omics and imaging data) will be provided with personalised (3D printed) smart implants that restore the hampered blood supply enabling cellular self-organization to regenerate defects that do not heal otherwise. Genevention will develop a digital platform for omics data management and 3D implant optimization based on semantic data integration technologies, analysis plugins for modeling and simulation and intuitive interfaces for clinical use cases.

Of all genetic mutations causing human disease, approximately 11% are nonsense mutations, also termed premature termination codons (PTCs). In these mutations, a codon that codes for an amino acid is changed into a stop codon, preventing translation of the complete, functional protein. This type of mutation can be found in nearly all known monogenetic diseases including most rare diseases, summing up to 5,000–10,000 diseases or tens of million patients worldwide. It is a viable yet challenging therapeutic strategy to treat these PTCs with translational read­through-inducing drugs (TRIDs). These compounds stimulate the ribosome to interpret the PTC as a sense codon and thereby to restore part of the production of the normal length gene product. TRIDs are important from a clinical point of view, as they may lead to new and improved personalized medicine approaches that will match certain patients in affected genes with more specific drugs. Together with Dr.Sven Thoms from the University Medical Center Göttingen and Prof. Rina Rosin-Arbesfeld from Tel Aviv University,the project will investigate nonsense mutations in the Adenomatous Polyposis Coli (APC) gene, which is mutated in the vast majority (over 80%) of both hereditary and sporadic colorectal cancers(CRCs). Genevention will develop algorithms to characterize the Stop Codon sequence context of APC mutations and predict which TRIDs will most efficiently restore APC expression to help developing therapeutic approaches. Funding for the project has been acquired in terms of a grant by the German-Israeli Foundation for Scientific Research and Development (GIF I-89-412.20-2017). We are looking forward to this exciting research collaboration and hope to provide useful tools and algorithms to pave the way for individualized Stop codon readthrough therapy!