Research ArticleRare Diseases

Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice

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Science Translational Medicine  18 Sep 2013:
Vol. 5, Issue 203, pp. 203ra124
DOI: 10.1126/scitranslmed.3006247

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Receptor Decoy Restores Bone Growth

Achondroplasia is a rare disease where bone growth is stunted and cartilage does not form correctly. It is caused by a mutation in the gene that encodes fibroblast growth factor receptor 3 (FGFR3), which leads to overactive receptor signaling. Yet, despite knowing the cause, a treatment has not been discovered. In an innovative approach, Garcia and colleagues used receptor “decoys” to prevent the FGF ligand from binding its mutated receptor, thus interrupting the signaling cascade and restoring bone growth in mice.

Normal mice or mice with the mutation in the gene encoding FGFR (Fgfr3ach/+) were treated with recombinant, soluble FGFR3 (sFGFR3) or a vehicle control for 3 weeks. More than 60% of Fgfr3ach/+ mice that were left untreated died during the treatment period, whereas only 12% of sFGFR3-treated mice died from achondroplasia-related complications, such as respiratory distress or paraplegia. In the surviving Fgfr3ach/+ animals, those treated with sFGFR3 had normal body and tail lengths, normal rib cage development, and decreased spinal and skull deformities—all similar to their healthy, wild-type counterparts. Untreated transgenic animals suffered from the defects common to achondroplasia: shortened stature, abnormal rib cage structure, and spinal compression, leading to paraplegia and bladder dysfunction.

The sFGFR3 therapy was not toxic to the animals and did not affect reproduction (in fact, by increasing pelvis size in treated transgenic females, litter sizes were normal). Additional preclinical studies will be needed to see if this is a viable long-term treatment for achondroplasia, but with a long half-life and promising early outcomes in animals, this FGFR decoy may be a viable postnatal treatment for translation.

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