Project Details
Projekt
Clinical assessment of inherited low bone mineral density disorders from infancy to adolescence
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
In the context of the clinical research unit ProBone (“Precision Medicine for Early-Onset Low Bone Mineral Density Disorders”), this project (P2) focusses on the identification and clinical characterization of patients with childhood-onset low bone mineral density (BMD) disorders. The relevance of P2 is based on the fact that a substantial number of genetically tested adult patients with early-onset low BMD were identified to display an attenuated form of an inherited childhood skeletal disorder, such as osteogenesis imperfecta or hypophosphatasia. Moreover, since one of the adult patients with early-onset low BMD, identified in the context of the National Bone Board (ProBone project P1), was genetically diagnosed with mucopolysaccharidosis type I (pathogenic compound heterozygous variants in the IDUA gene), there is a necessity to apply a full osteologic assessment for individuals with distinct lysosomal storage disorders. This is also important, since we have previously identified another group of patients, carrying pathogenic variants in the GNPTAB gene (causing mucolipidosis type II or III), in whom increased bone resorption biomarkers were identified. The first aim of P2 is to ensure a complete skeletal assessment of patients with childhood-onset low BMD, including children with distinct lysosomal storage and other metabolic disorders, for which the bone remodeling status has never been systematically analyzed. Since a large number of patients admitted to the Children´s Hospital (also including patients with infantile hypophosphatasia) are treated by established enzyme replacement therapies, P2 will also address the clinically relevant question, if existing bone remodeling pathologies are improved by enzyme replacement, which is so far essentially unknown, at least for lysosomal storage disorders. Finally, P2 will follow a molecular biology approach to target the most common pathogenic variant (c.3503_3504del) in the GNPTAB gene, which causes the severe childhood disorder mucolipidosis type II. More specifically we will apply an exon-skipping approach with antisense oligonucleotides, performed in close collaboration with the ProBone project P4, which can also provide a proof-of-principle for similar therapeutic concepts in the context of other genetic low BMD disorders. Supported by specific interactions with the other ProBone partners, we expect to obtain substantial novel knowledge for genetically caused early-onset low BMD disorders and to ensure an early disease diagnosis and treatment of affected children and adolescents. Moreover, P2 will establish an interdisciplinary outpatient clinic and a new patient registry for pediatric low BMD disorders, which will strongly improve the existing infrastructure and also ensure an optimal transition from pediatric into adult patient care.
DFG Programme
Clinical Research Units
