Achondroplasia is an autosomal dominant disorder characterized by dwarfism and disproportionate shortness of limbs, accompanied by life-altering complications. Achondroplasia is caused by a gene alteration (mutation) in the FGFR3 gene.
Approximately 97% of achondroplasia cases are caused by a single mutation in the fibroblast growth factor receptor 3 (FGFR3), a G380R substitution which results in a ligand dependent gain of function. This leads FGFR3 to send persistent rather than transient growth inhibition signals, preventing its down-regulation. The ensuing disrupted endochondral ossification results in disproportionate shortness of limbs, and is associated with debilitating orthopedic, neurological and ENT (Ear Nose and Throat) complications.
This rare condition affects approximately 1 in 25,000 live births.
Children are typically diagnosed at birth, but increasingly parents are finding out via prenatal ultrasounds. Currently, the only available therapeutic option for achondroplasia is limb lengthening, an extremely invasive surgical procedure that addresses height but not other achondroplasia-associated complications.
Mechanism of Action for TA-46 in Achondroplasia
Normal bone growth
elimination of activated receptor
In Achondroplasia
activated receptor not eliminated always “on”
sFGFR3 decoy strategy
competition preventing ligand binding and membrane-bound receptor dimersation (receptor not turned “on”)
In Other Words...
Imagine you're driving a car and you want to go faster to keep up with traffic. However, for some reason the car won't accelerate. Something is pushing the brake pedal down, not allowing you to keep up with the other cars. Suddenly, something unlocks, the brake pedal is loosened, and the car is able to reach its cruising speed potential.
That is what we want to do, unlock the growth potential to restore normal bone growth and development.
More than 80% of children with drawfism have average height parents and siblings.
The most frequenly diagnosed cause of genetically determined short stature is achondroplasia, a genetic condition that results in disroportionately short arms and legs
The average height of an adult with dwarfism is 4’0/122 cm, but typical heights rangeform 2’8/8’2cm to 4’8/142cm
Publications
- Celine Saint-Laurent, Stephanie Garcia, Vincent Sarrazy, Karine Dumas, Florence Authier, Sophie Sore, Albert Tran, Philippe Gual, Isabelle Gennero, Jean-Pierre Salles, Elvire Gouze (2018) Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia. Online PLOS ONE
- Garcia, S., Dirat, B., Tognacci, T., Rochet, N., Mouska, X., Bonnafous, S., Patouraux, S., Tran, A., Gual, P., Le Marchand-Brustel, Y., Gennero, I., and Gouze, E. (2013) Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice. Science Translational Medicine 5, 203ra124
- Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J. M., Maroteaux, P., Le Merrer, M., and Munnich, A. (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252-254
- Donaldson, J., Aftab, S., and Bradish, C. (2015) Achondroplasia and limb lengthening: Results in a UK cohort and review of the literature. J Orthop 12, 31-34
- Ireland, P.J., Pacey, V., Zankl, A., Edwards, P., Johnston, L. M., and Savarirayan, R. (2014) Optimal management of complications associated with achondroplasia. Appl Clin Genet 7, 117-125
- Unger, S., Bonafe, L., Gouze, E. (2017) Current care and investigational therapies in achondroplasia. Curr Osteoporosis Report 14, in press.