Meclizine / meclozine for achondroplasia?

Old drugs, new tricks

On last September, we have reviewed in this previous article the work presented by Matsushita and coworkers about the potential use of meclizine in achondroplasia, during the last edition of the International Skeletal Dysplasias Society Meeting, held in Bologna, Italy. (1) Now, their complete work has just been published in PLoS ONE. (2)

In the context of the recently launched strategy of searching for repositioning of old drugs that has been explored by several academic institutions and industries (see this article), Matsushita's group has identified meclizine from a list of more than one thousand drugs approved by FDA, as having potential use for achondroplasia. (2)  

In brief, meclizine/meclozine is an old OTC drug, commonly used to treat motion sickness. It has been in the market for more than 50 years, so has a well known safety profile. The authors concluded that meclizine has the potential to be used in achondroplasia. So, let's take a look at their work.

Meclizine reduces FGFR3 signaling effects

As we saw in the abstract presented in the ISDS, the authors demonstrated that meclizine attenuated the effects of the fibroblast growth factor receptor 3 (FGFR3) signaling, thus ameliorating bone growth in their experiments. They tested meclizine effects in three different kinds of cells and also in mouse bone explants. There were no tests made in living animals.

All the tests performed showed that meclizine reduced the activity of the most relevant enzymatic cascade linked to FGFR3 signaling in chondrocytes, the mitogen-activated protein kinase (MAPK) cascade (Figure 1*), which is thought to be a key player causing bone growth arrest seen in achondroplasia. Furthermore, they also tried to identify how meclizine would be working in the MAPK cascade and found that it is likely to be inhibiting this cascade at the level of ERK (Figure 1), although they couldn't explain the exact mechanism involved.

Figure 1. FGFR3 - MAPK cascade and potential site of action of meclizine/meclozine

Matsushita M et al. (2013). PLoS ONE 8(12): e81569. doi:10.1371/journal.pone.0081569. Reproduced here for illustration purposes only.

The figure above also shows the site of actions of other molecules cited in the text, such as the tyrosine kinase inhibitors NF449 (3) and A31 (4) and the peptide P3 (5), compounds we have also mentioned or reviewed here in the blog, as well as the CNP mode of action.

Bones exposed to meclizine and CNP grow more than those not exposed

Matsushita et al. demonstrated that bones exposed to meclizine and to C-type natriuretic peptide (CNP) grew more than the matching controls, not exposed (Figure 2). Note the pictures showing the effect of the FGFR3 ligand FGF2 and the counteracting, positive effects on bone growth of both CNP and meclizine. Interestingly, as also noted by the authors, even bones not exposed to FGF2 grew more with meclizine. Noteworthy, this study also provides even more evidence for the positive effect of CNP in bone growth. 


Figure 2. 

Meclozine increases the longitudinal length of embryonic tibiae with or without FGF2 treatment in bone explant culture. Unstained bilateral tibiae of the same individual were photographed side by side on day six of explant culture. Longitudinal bone lengths were normalized to that of untreated contralateral tibia, and the mean and SD are indicated. FGF2 causes inhibition of longitudinal bone growth. In the presence of FGF2, CNP (0.2 µM) and meclozine (20 µM) significantly increased the longitudinal length of embryonic tibiae. Even without FGF2, meclozine (20 µM) facilitated the growth of embryonic tibiae but without statistical significance (Student's t-test).doi:10.1371/journal.pone.0081569.g004

 
Is there a future for meclizine in achondroplasia?

The authors say that given the effects observed with meclizine in their experiments, this compound could be used alone or in addition to CNP to help rescuing bone growth in achondroplasia. They recognize, both in the paper and also in the press release published to divulge their work (2,6) that, before starting giving meclizine to children, its safety profile must be addressed first, and that the effect of meclizine observed in vitro, must be explored also in an appropriate animal model (in vivo) before going to the clinic. (6)

These observations are important because currently, at least in US, meclizine is only approved for age 12 and older, as there is no enough information about its use in younger children. Given that meclizine has a number of other effects in the body, a thorough assessment on its safety in younger children is warranted.

Concluding

Although promising, before thinking in start giving meclizine for children with achondroplasia, more work must be done. It is not uncommon that compounds with potential to become medicines identified in in vitro experiments fail to do so in living models. For achondroplasia, it is key to see how a potential therapy will work in vivo, because the cartilage growth plate can be a formidable barrier for large compounds. No drug is exempt of potential side effects, and they must show to have a well balanced safety/risk profile, especially if it is supposed to be given for years to a developing body.

As a final note, the potential availability of acessible drugs for the treatment of rare conditions such as achondroplasia opens a new perspective for patients and governments. One of the major challenges to develop new therapies for rare diseases is exactly the high cost to be paid to have them available (reviewed here).


* Disclosure: figures shown in this article come from the original article from Matsushita et al., as published in PLoS ONE website, and are made freely available by the journal editors. They are reproduced here with the only purpose of illustration and the source is due cited.

References

1. Matsushita et al. Meclozine facilitates chondrocyte proliferation and differentiation by attenuating abnormally activated fibroblast growth factor receptor 3 (FGFR3) signaling in achondroplasia. Presented at the 11th International Skeletal Dysplasias Society Meeting, August 28-31, 2013, Bologna, Italy.

2. Matsushita M et al. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS ONE 2013 8(12): e81569. doi:10.1371/journal.pone.0081569. Free access.

3. Jonquoy A et al. A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. Hum Mol Genet 2012;21(4):841-51. doi: 10.1093/hmg/ddr514. Free access.

4. Krejci P et al. NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells. J Biol Chem. 2010; 285(27): 20644-53. Free access.

5. 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; 21(26): 5443-55.

6. Press Release. Nagoya University Graduate School of Medicine. 2013.12.05　Drug repositioning of an OTC drug for motion sickness, Meclozine, for short stature patients.