Abstract
Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.
Highlights
Achondroplasia (ACH) is one of the most common skeletal dysplasias characterized by severe short stature with rhizomelic shortening of the extremities, relative macrocephaly with frontal bossing, midface hypoplasia, and increased lumbar lordosis[1]
We identified that meclozine, an anti-histamine drug that has been used as an anti-motion-sickness for more than 50 years, inhibited fibroblast growth factor receptor 3 (FGFR3) signaling in various chondrocytic cell lines[15]
We first demonstrated that Cmax and area under the concentration-time curve (AUC) after single dose of 2 mg/kg of meclozine in mice was lower than those after single dose of 25 mg tablet used in human[17], and confirmed that this dose is clinically relevant
Summary
Achondroplasia (ACH) is one of the most common skeletal dysplasias characterized by severe short stature with rhizomelic shortening of the extremities, relative macrocephaly with frontal bossing, midface hypoplasia, and increased lumbar lordosis[1]. Recombinant human growth hormone has been administered for short stature in ACH children in some limited countries[8], but the response to this therapy is moderate and the long-term effects remain controversial. Distraction osteogenesis is another therapeutic option to gain longitudinal bone length but it needs significant time and efforts associated with higher rates of complications[9]. Oral administration of ad libitum intake of meclozine-containing foods increased longitudinal bone growth in ACH mouse model[16]. We further demonstrated additional FGFR3 inhibitory effects of this drug on bone volume and bone quality
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