Journal of Genetic Syndromes & Gene Therapy
Open Access

A novel in vitro platform for the screening of therapeutics for the treatment of hereditary osteoblastdependent disorders

Annual Congress on Rare Diseases & Orphan Drugs

October 26-27, 2016 Chicago, USA

Dimitra Micha

Vrije Universiteit Medical Centre, Netherlands

Posters & Accepted Abstracts: J Genet Syndr Gene Ther

Abstract :

The treatment of hereditary bone-related disorders, depending on osteoblast dysfunction, currently poses severe limitations. Despite the identification of the causative mutations of many diseases and subsequent understanding of the disease mechanism, treatment is limited to the alleviation of symptoms accompanying disease presentation. Given the rarity of bone biopsy acquisition and the technical complexities of iPSCs, a faithful in vitro model based on patient derived cells is still lacking. A novel in vitro model based on growth factor induced osteogenic transdifferentiation of primary human dermal fibroblasts is shown to be appropriate to study diseases affecting osteoblast differentiation and/or function. Two rare hereditary bone-related diseases, fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI) provide a paradigm for the application of this model with regard to investigating the disease mechanism and screening of novel therapeutics. FOP is caused by a mutation in the activin receptor IA (ACVR1) gene which leads to aberrant bone morphogenetic protein signaling. Heterotopic ossification arises from flare-ups, which are inflammation episodes leading to the irreversible replacement of connective tissue with bone. In addition to making possible the study of the mechanism leading to heterotopic ossification this model aided in the identification of transforming growth factor �² (TGF�²) as a novel target of treatment. Moreover, this model has provided the platform for the screening of additional candidate inhibitors of heterotopic ossification. The majority of OI cases are caused by mutations in COL type-I genes resulting in reduced collagen production in bone which leads to high bone fragility. The use of patient derived transdifferentiated osteoblasts gives the opportunity to investigate agents targeting collagen production which is the primary disease defect. The feasibility of this model, in combination with the use of primary patient cells, paves the pathways for the testing of novel therapeutics and regenerative medicine aiming the cure of hereditary osteoblast-dependent disorders.

Biography :

Email: d.micha@vumc.nl