Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Further we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in mice model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, in order to elucidate whether or not the systemic administration of CNP is the novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter, or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by intravenous administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans.
Abstract Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1–PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.
Abstract Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis ( AD ). In mice, interleukin ( IL )‐31 and its receptor IL ‐31 receptor A ( IL ‐31 RA ) are known to play a critical role in pruritus and the pathogenesis of AD ; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL ‐31 in primates. We showed that administration of cynomolgus IL ‐31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti‐human IL ‐31 RA monoclonal antibody that also neutralizes cynomolgus IL ‐31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL ‐31‐induced scratching for about 2 months. These results suggest that the IL ‐31 axis and IL ‐31 RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL ‐31 signalling by an anti‐human IL ‐31 RA antibody is a promising therapeutic approach for treatment of AD . Nemolizumab is currently under investigation in clinical trials.
