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

LOS PACIENTES AVANZANDO EN INVESTIGACIÓN

Iniciativas dirigidas por pacientes y acciones para fomentar la investigación de las enfermedades raras Gracias a la financiación del Téléthon francés para la identificación genética, los investigadores están desarrollando una terapia para la acondroplasia

Sci Transl Med 18 September 2013:
Vol. 5, Issue 203, p. 203ra124
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006247

• Research Article

RARE DISEASES

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

1. Stéphanie Garcia¹,²,³,
2. Béatrice Dirat¹,³,
3. Thomas Tognacci¹,³,
4. Nathalie Rochet⁴,
5. Xavier Mouska⁴,
6. Stéphanie Bonnafous¹,³,⁵,
7. Stéphanie Patouraux¹,³,⁶,
8. Albert Tran¹,³,⁵,
9. Philippe Gual¹,³,⁵,
10. Yannick Le Marchand-Brustel¹,³,
11. Isabelle Gennero⁷ and
12. Elvire Gouze¹,³,*

+ Author Affiliations

1. ¹INSERM, U1065, Team 8, Mediterranean Center for Molecular Medicine, 06204 Nice, France.
2. ²University of Paul Sabatier Toulouse III, 31062 Toulouse, France.
3. ³University of Nice-Sophia Antipolis, 06100 Nice, France.
4. ⁴UMR CNRS 7277, INSERM U1091, Valrose Biology Institute, University of Nice Sophia Antipolis, 06108 Nice, France.
5. ⁵Department of Digestive Diseases, University Hospital Center of l’Archet, 06202 Nice, France.
6. ⁶Department of Biology, University Hospital Center of l’Archet, 06202 Nice, France.
7. ⁷INSERM, U1043, Center of Physiopathology of Toulouse Purpan, 31024 Toulouse, France.

1. ↵*Corresponding author. E-mail: elvire.gouze@inserm.fr

Abstract

Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3^ach/+ mice—the mouse model of achondroplasia—twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3^ach/+ mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders.

• Copyright © 2013, American Association for the Advancement of Science

Citation: S. Garcia, B. Dirat, T. Tognacci, N. Rochet, X. Mouska, S. Bonnafous, S. Patouraux, A. Tran, P. Gual, Y. L. Marchand-Brustel, I. Gennero, E. Gouze, Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice. Sci. Transl. Med. 5, 203ra124 (2013).

Read the Full Text

The editors suggest the following Related Resources on Science sites Back to Top

In Science Translational Medicine

• Research Article: Cancer Blockade of Nonhormonal Fibroblast Growth Factors by FP-1039 Inhibits Growth of Multiple Types of Cancer

  • Thomas C. Harding,
  • Li Long,
  • Servando Palencia,
  • Hongbing Zhang,
  • Ali Sadra,
  • Kevin Hestir,
  • Namrata Patil,
  • Anita Levin,
  • Amy W. Hsu,
  • Deborah Charych,
  • Thomas Brennan,
  • James Zanghi,
  • Robert Halenbeck,
  • Shannon A. Marshall,
  • Minmin Qin,
  • Stephen K. Doberstein,
  • Diane Hollenbaugh,
  • W. Michael Kavanaugh,
  • Lewis T. Williams,
  • and Kevin P. Baker

  Sci Transl Med 27 March 2013 5:178ra39
  • Editor's Summary
  • Abstract
  • Full Text
  • Full Text (PDF)
  • Supplementary Materials
• Perspective: Metabolic Disease Receptor Antibodies as Novel Therapeutics for Diabetes

  • Siegfried Ussar,
  • Sara G. Vienberg,
  • and C. Ronald Kahn

  Sci Transl Med 14 December 2011 3:113ps47
  • Abstract
  • Full Text
  • Full Text (PDF)
• Research Article: Osteoarthritis Teriparatide as a Chondroregenerative Therapy for Injury-Induced Osteoarthritis

  • Erik R. Sampson,
  • Matthew J. Hilton,
  • Ye Tian,
  • Di Chen,
  • Edward M. Schwarz,
  • Robert A. Mooney,
  • Susan V. Bukata,
  • Regis J. O’Keefe,
  • Hani Awad,
  • J. Edward Puzas,
  • Randy N. Rosier,
  • and Michael J. Zuscik

  Sci Transl Med 21 September 2011 3:101ra93
  • Editor's Summary
  • Abstract
  • Full Text
  • Full Text (PDF)
  • Supplementary Materials
• Research Article: Aging Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans

  • Jaime Guevara-Aguirre,
  • Priya Balasubramanian,
  • Marco Guevara-Aguirre,
  • Min Wei,
  • Federica Madia,
  • Chia-Wei Cheng,
  • David Hwang,
  • Alejandro Martin-Montalvo,
  • Jannette Saavedra,
  • Sue Ingles,
  • Rafael de Cabo,
  • Pinchas Cohen,
  • and Valter D. Longo

  Sci Transl Med 16 February 2011 3:70ra13
  • Editor's Summary
  • Abstract
  • Full Text
  • Full Text (PDF)
  • Supplementary Materials
• Research Article: Bone Wnt Proteins Promote Bone Regeneration

  • Steven Minear,
  • Philipp Leucht,
  • Jie Jiang,
  • Bo Liu,
  • Arial Zeng,
  • Christophe Fuerer,
  • Roel Nusse,
  • and Jill A. Helms

  Sci Transl Med 28 April 2010 2:29ra30
  • Editor's Summary
  • Abstract
  • Full Text
  • Full Text (PDF)
  • Supplementary Material
• Perspective: Osteoporosis β-Arrestin–Biased Parathyroid Hormone Ligands: A New Approach to the Development of Agents that Stimulate Bone Formation

  • Serge L. Ferrari and
  • Mary L. Bouxsein

  Sci Transl Med 7 October 2009 1:1ps1
  • Summary
  • Full Text
  • Full Text (PDF)