Friday, October 12, 2012

A newly identified peptide blocks FGFR3 and rescue growth in a tanatophoric dysplasia mouse model

New therapeutic strategy for achondroplasia on stage

Researchers from China and US identified a new peptide (a molecule made of amino acids) that is capable to bind to the extracellular part of the fibroblast growth factor receptor type 3 (FGFR3) and to block the receptor activity in mice bearing the mutation that causes tanatophoric dysplasia type II (TDII).

TDII is caused by a mutation in FGFR3 which produces a more severe form of growth arrest compared to achondroplasia and is lethal to the affected individual.

In the study by Jin et al. mice pups bearing the TDII mutation were exposed to the peptide called P3 during the pregnancy and have significant recovery of several aspects of the growth arrest caused by the overacting FGFR3. They grew more, have their growth plates resembling those of normal controls and survived much longer than those not treated. 


This study is interesting because showed that a relatively simple to obtain compound made of amino acids was capable to reach FGFR3 inside the growth plate and to produce a significant reduction in the receptor activity (or signaling, as researchers say). They tested a model of TDII, which is much more severe than achondroplasia. This means that we could expect even more significant effects of the treatment in achondroplasia.

Based on what is described in this study and reflecting about the possible mechanism of action of this peptide, it looks like it would interefere with the ligand-receptor binding (a ligand = a FGF) and/or with the dimerization process. Dimerization is the phenomenon that takes place when two close FGFR3 are bound to FGFs and couples, leading to the conformational adjustment that will expose their internal active parts and generate the intracellular signaling. For more information about this mechanism, you could follow this link, to a previous article of this blog.

The authors also mention that they didn’t identify any other disorder in other tissues that could be associated to the treatment with P3. This is relevant because it implies that FGFR3 would have it main post-natal effects only in bones. For any therapy directed against FGFR3 is good to know that there will be no extra- target effects (the target here is the growth plate).

In the words by a renowned investigator of FGFR3-related chondrodysplasias, we are coming to a time, in the near future, where we will be not anymore debating about having or not a therapy for achondroplasia. The debate will be about which one we will choose. 


Jin M et al. A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Hum Mol Genet. 2012 Oct 9. [Epub ahead of print]

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