ICCBH2019 Poster Presentations (1) (226 abstracts)
TA-46 prevents premature synchondrosis and restores foramen magnum size in a mouse model of achondroplasia
Stephanie Garcia 2 , Guylene Rignol 2 , Diogo Goncalves 2 , Pierre Dellugat 2 , Lionel Tosello 2 , Raphael Marsault 2 , Jeff Stavenhagen 3 , Luca Santarelli 3 & Elvire Gouze 1
1INSERM, Nice, France; 2Therachon SAS, Nice, France; 3Therachon AG, Basel, Switzerland.
Objectives: Achondroplasia, the most common form of short limb dwarfism, is a rare genetic disorder caused by a gain-of-function mutation of the FGFR3 receptor (FGFR3-G380R) and there are currently no effective treatments available. We have developed TA-46, a recombinant human soluble FGFR3(sFGFR3) form of the FGFR3 cell surface receptor containing an extra-cellular ligand-binding domain, including three IgG domains, which confer binding specificity. TA-46 is designed to block activation of the FGFR3-G380R receptor responsible for achondroplasia, thereby directly addressing the skeletal defect. TA-46 exerts its effects as either a ligand ‘trap,’ competing for the natural FGF ligands, or through formation of an inactive heterodimer with FGFR3 or FGFR3-G380R on the cell surface. To elucidate the potential therapeutic benefit of TA-46, we characterized its impact on skull synchondroses in a mouse model of achondroplasia carrying the mouse equivalent to the human G380R mutation (Fgfr3ach/+).
Methods: TA46 was injected subcutaneously at a dose of 10 mg/kg to newborn Fgfr3ach/+ mice – the mouse model of achondroplasia – twice per week throughout the growth period during three weeks. Longitudinal skull measurements were performed by X-rays were imaging at post-natal day 3, 9 and 22.
Results: Treatment with TA-46 compared with vehicle control prevented premature synchondrosis ossification and extended the period of bone formation in Fgfr3ach/+ mice. Treatment with TA-46 restored the foramen magnum to normal size and resulted in improved skull shape and cranium ratio. TA-46 was also associated with improved survival, body weight, and skeletal endochondral bone growth (body and tail length).
Conclusions: Given the impact of TA-46 on synchondrosis closure, it has the potential to prevent some of the most severe complications of achondroplasia if used early enough during bone development. These data support the clinical development of TA-46 for achondroplasia, and suggest that early treatment may be required to best address impaired endochondral bone growth.
Disclosure: Authors are employees and/or shareholders of Therachon, the company developing TA-46.
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Bone Abstracts
ISSN 2052-1219 (online)
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