GENECELLTHER

Development of biotherapies for growth plate disorders

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 Obiettivo del progetto (Objective)

'Skeletal dysplasias are a diverse and heterogeneous group of hereditary disorders characterized by malformations of bone and cartilage. These conditions affect development patterns in bones of growing children, and the clinical severity ranges from mild short stature to highly disfiguring, and even to lethal forms. Their treatment is very challenging, typically with no or limited success. This proposal is designed to explore the use of gene- and stem cell-based approaches to influence bone development in growth plate disorders characterized by aberrant constitutive cellular signaling in the growth plate chondrocytes. These biotherapeutic technologies offer the unique opportunity to manipulate and influence the cells in the developing growth plate, and if successfully applied, may functionally rescue bone growth and restore normal skeletal development. In this study, we will work to gain fundamental knowledge necessary for the rational design of a therapy for achondroplasia and Noonan syndrome. In attempting to address skeletal dysplasias, we have chosen to focus on these diseases because they are caused by gain-of-function point mutations affecting intracellular signaling in growth plate chondrocytes, and there exists transgenic mouse models containing mutations identical to that found in affected patients. The following specific aims will be addressed: Aim 1- To determine the biological effects of systemic gene delivery and overexpression of sFGFR3 in Fgfr3ach/ mice. Aim 2- To determine if overexpression of sFGFR3 or inhibition of SHP2 expression can restore growth in bones from Ptpn11D61G/ mice in an organ culture system. Aim 3- To determine the capacity of exogenous stem cells to influence the biology of diseased growth plate in vivo. The fellowship will contribute to the reintegration of Dr. Gouze, an expert in gene and stem cell therapies for musculoskeletal disorders, in the INSERM unit of Pr. Salles, an expert in pediatric endocrinology and growth disorders'

Introduzione (Teaser)

A European study explored an innovative therapeutic intervention for children suffering from achondroplasia, a rare genetic disorder which causes dwarfism. The nature of the approach makes it feasible to be implemented in the clinic.

Descrizione progetto (Article)

Achondroplasia occurs due to a mutation in the gene for fibroblast growth factor receptor 3 (FGFR3). The disorder may be inherited as an autosomal dominant trait where a defective gene from one parent will cause this disorder in the child. However, the majority of the cases of achondroplasia are initiated by spontaneous mutations.

Affected children have abnormal cartilage formation and long-bone development, resulting in short stature. In the most severe cases, they can suffer from deformations of the skull and vertebrae which lead to neurological and orthopaedic complications. Currently there is no treatment for achondroplasia.

Scientists on the EU-funded 'Development of biotherapies for growth plate disorders' (GENECELLTHER) project proposed gene therapy for treating children with achondroplasia. They hoped to block the overactivation the mutant receptor through genetic manipulation of the cells in the developing growth plate and thus restore normal skeletal development. For safety concerns, the gene therapy approach was replaced by a recombinant protein therapy.

In this context, they used a transgenic mouse model lacking FGFR3 expression to test a recombinant protein approach. Treated animals exhibited improved bone formation suggesting that the intracellular signalling in growth plate chondrocytes can be blocked.

These promising results clearly indicated that the provision of a decoy protein at the right stage during development may restore the inherited defect. The approach also offered the advantage that the protein could be applied systemically, making it clinically feasible for infants.

Overall, the GENECELLTHER study pioneered the way for the therapy of skeletal defects. Although the toxicity of the administered protein needs to be determined, the proposed strategy offers hope for the treatment of other developmental defects.