Achondroplasia, the most common form of short-limb dwarfism, occurs in approximately 1 in 30,000 live births. Affected children suffer from abnormal long bone development and deformations of the vertebrae and bones in the skull. There is no cure for achondroplasia, and existing treatments only address some of the complications. Achondroplasia is caused by a mutation in the transmembrane region of fibroblast growth factor receptor-3 (FGFR3). Wild type FGFR3 is one of many inhibitory regulators of endochondral bone growth, and following interaction with FGF ligand acts negatively on both proliferation and terminal differentiation of growth plate chondrocytes. In 98% of those with achondroplasia, the phenotype is caused by a specific point mutation in FGFR3, resulting in the substitution arginine for glycine at position 380 (Gly380Arg). This mutation is one of """"""""gain-of-function,"""""""" i.e. increased ligand-mediated signaling of FGFR3, which leads to excessive inhibition of bone growth. Similar to the treatment of rheumatoid arthritis through the systemic administration of soluble receptors for tumor necrosis factor 1, we hypothesized that systemic delivery of a soluble FGFR3 molecule would likewise titrate receptor-specific FGF ligands and thereby reduce aberrant FGFR3 signaling to rescue bone growth. Initial experiments in a murine model of achondroplasia generated by transgenic insertion of the murine orthologue of the mutant FGFR3 gene (FGFR3G374R), have shown great promise. Gene delivery of a naturally-occurring, secreted isoform of FGFR3 (FGFR3?TM) to the quadriceps of neonatal achondroplastic mice was found to provide sustained release of FGFR3?TM into the circulation. Appropriate dosing of the gene delivery vector generated levels of circulating FGFR3?TM sufficient to rescue bone growth, such that treated mice were essentially indistinguishable in size from normal littermates at four weeks. The transgenic model has been extremely useful in our proof-of-concept studies. However, certain features may unnaturally influence the amplitude of the biological response to treatment with FGFR3?TM. Therefore, to explore the treatment potential of soluble FGFR3 inhibitors in a context more relevant to the human achondroplasia mutant genotype and phenotype, we will extend these investigations to include the murine FGFR3G374R knock-in achondroplasia model. We will address issues relevant to the mechanisms supporting rescue of skeletal growth and to the potential clinical application of this treatment approach. We will address the following Specific Aims: (1) To determine the capacity of FGFR3?TM to bind FGF-ligand and thereby inhibit aberrant FGFR3G374R signaling in growth plate chondrocytes from transgenic and knock-in models of achondroplasia. (2) To determine the effects of long-term delivery of FGFR3?TM on the skeletal growth and physiology of the FGR3G374R knock-in achondroplasia model. (3) To determine the capacity of administration of a recombinant soluble FGFR3 to rescue bone growth in FGFR3G374Rneo-/+ mice. (4) To determine the relationship between age of intervention and the magnitude of the skeletal response following treatment with soluble FGFR3.

Public Health Relevance

Achondroplasia is the most common form of short-limbed dwarfism. In 98% of cases it is caused by a single genetic mutation in fibroblast growth factor receptor 3 (FGFR3), which regulates the growth of chondrocytes in the growth plates of long bones. The present study is designed to explore a treatment for achondroplasia based on the systemic delivery of soluble forms of FGFR3 that will block the effects of this mutation and restore normal bone growth.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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University of Florida
Schools of Medicine
United States
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Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2018) Gene Delivery to Joints by Intra-Articular Injection. Hum Gene Ther 29:2-14
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