Gene therapy for achondroplasia
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.
Keywords
Achondroplasia, dwarfism, FGFR3, gene therapy, recombinant protein, chondrocyte, toxicity
