RESUMO
INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.
Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Criança , Humanos , Peptídeo Natriurético Tipo C/uso terapêutico , Atenção à Saúde , Manejo da Dor , Acondroplasia/tratamento farmacológicoRESUMO
BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.
Assuntos
Acondroplasia , Gastroenterite , Feminino , Humanos , Lactente , Masculino , Acondroplasia/tratamento farmacológico , Método Duplo-Cego , Peptídeo Natriurético Tipo C/uso terapêutico , Pré-EscolarRESUMO
INTRODUCTION: Vosoritide is the first approved pharmacological treatment for achondroplasia and is indicated for at-home injectable administration by a trained caregiver. This research aimed to explore parents' and children's experience of initiating vosoritide and administering this treatment at home. METHODS: Qualitative telephone interviews were conducted with parents of children being treated with vosoritide in France and Germany. Interviews were transcribed and analysed using thematic analysis. RESULTS: Fifteen parents participated in telephone interviews in September and October 2022. The median age of children in this sample was 8 years old (range 3-13 years) and children had been taking treatment from 6 weeks to 13 months. Four themes document families' experience with vosoritide: (1) awareness of vosoritide treatment, uncovering that parents first heard of vosoritide through their own research, patient advocacy groups, or through their physicians; (2) treatment understanding and decision-making, which found that their decision to take treatment is based on a desire to relieve future medical complications and increase height for improved independence, and they consider the extent to which the treatment has severe side effects; (3) training and initiation, which showed that the hospital initiation and training sessions varied considerably both across and within countries, with different treatment centres taking different approaches; and (4) managing treatment at home brings psychological and practical challenges, which are ultimately overcome with perseverance and available support. CONCLUSIONS: Parents and children are resilient to challenges posed by a daily injectable treatment and highly motivated to improve their quality of life. Parents are prepared to overcome short-term treatment challenges for future gains in terms of health and functional independence for their children. Greater support could ensure they have the right information to initiate treatment and manage treatment at home, which will improve parents' and children's experience.
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Acondroplasia , Qualidade de Vida , Criança , Humanos , Recém-Nascido , Pais/psicologia , Peptídeo Natriurético Tipo C/uso terapêutico , Acondroplasia/tratamento farmacológico , Pesquisa QualitativaRESUMO
Achondroplasia is the commonest form of dwarfism and results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. The mutation is at nucleotide 1138 resulting in a G-to-A transition (134934.0001). This condition is characterized by full penetration meaning that everyone with this genetic mutation will exhibit the phenotypic characteristics of achondroplasia. It is a gain-of function mutation that causes increased inhibition of cartilage formation. C-type natriuretic peptide (CNP) acts on the growth plate through the natriuretic peptide receptor-B (NPR-B) causing the transformation of guanosine 5'-triphosphate into cyclic guanosine monophosphate. However, CNP cannot be used in the treatment of achondroplasia because it is rapidly degraded by neutral endopeptidase. Vosoritide is a modified recombinant human CNP and has a half-life 10 times that of CNP. Clinical trials have demonstrated that vosoritide is effective in significantly increasing the annualized growth velocity in children with achondroplasia before the fusion of the epiphyses.
Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Criança , Humanos , Mutação , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/genética , Peptídeo Natriurético Tipo C/metabolismo , Peptídeo Natriurético Tipo C/uso terapêutico , NeprilisinaRESUMO
BACKGROUND AND OBJECTIVE: Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks). METHODS: Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. RESULTS: The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 µg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 µg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 µg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. CONCLUSIONS: The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. CLINICAL TRIALS REGISTRATION: NCT02055157, NCT03197766, and NCT01603095.
Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Acondroplasia/induzido quimicamente , Acondroplasia/tratamento farmacológico , Adolescente , Área Sob a Curva , Biomarcadores , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/farmacocinética , Peptídeo Natriurético Tipo C/uso terapêuticoRESUMO
Vosoritide (VOXZOGO®) is a modified recombinant human C-type natriuretic peptide (CNP) analogue, being developed by BioMarin Pharmaceutical for the treatment of achondroplasia. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which is a negative regulator of bone growth. Vosoritide acts to restore chondrogenesis through its binding to natriuretic peptide receptor B (NPR-B), resulting in the inhibition of downstream signalling pathways of the overactive FGFR3 gene. Vosoritide was approved in August 2021 in the EU for the treatment of achondroplasia in patients aged ≥ 2 years whose epiphyses are not closed; the diagnosis of achondroplasia should be confirmed by appropriate genetic testing. The drug is also under regulatory review in the USA for the treatment of achondroplasia and clinical development is underway in several countries. This article summarizes the milestones in the development of vosoritide leading to this first approval for achondroplasia in patients aged ≥ 2 years whose epiphyses are not closed.
Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Acondroplasia/genética , Adolescente , Área Sob a Curva , Peso Corporal , Criança , Pré-Escolar , Aprovação de Drogas , Europa (Continente) , Humanos , Taxa de Depuração Metabólica , Peptídeo Natriurético Tipo C/efeitos adversos , Peptídeo Natriurético Tipo C/farmacocinética , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Tipo C/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
PURPOSE: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. METHODS: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 µg/kg/day. RESULTS: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.
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Acondroplasia , Peptídeo Natriurético Tipo C , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Criança , Método Duplo-Cego , Humanos , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/uso terapêutico , Resultado do TratamentoRESUMO
Achondroplasia (ACH) is a disease caused by a missense mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.
Assuntos
Acondroplasia/terapia , Hormônio do Crescimento Humano/uso terapêutico , Peptídeo Natriurético Tipo C/análogos & derivados , Acondroplasia/genética , Acondroplasia/metabolismo , Acondroplasia/patologia , Animais , Humanos , Mutação de Sentido Incorreto , Peptídeo Natriurético Tipo C/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40.
Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Acondroplasia/complicações , Acondroplasia/tratamento farmacológico , Acondroplasia/cirurgia , Adulto , Criança , Pré-Escolar , Descompressão , Forame Magno/cirurgia , Humanos , Lactente , Recém-Nascido , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/uso terapêuticoRESUMO
BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.
Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Osteogênese , Absorciometria de Fóton , Acondroplasia/sangue , Adolescente , Biomarcadores/sangue , Estatura , Densidade Óssea , Criança , Pré-Escolar , Colágeno Tipo X/sangue , Método Duplo-Cego , Feminino , Humanos , Reação no Local da Injeção , Injeções Subcutâneas , Masculino , Peptídeo Natriurético Tipo C/uso terapêuticoRESUMO
BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
Assuntos
Acondroplasia/tratamento farmacológico , Crescimento/efeitos dos fármacos , Peptídeo Natriurético Tipo C/análogos & derivados , Osteogênese/efeitos dos fármacos , Acondroplasia/fisiopatologia , Adolescente , Biomarcadores/análise , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Colágeno/sangue , GMP Cíclico/urina , Relação Dose-Resposta a Droga , Feminino , Gráficos de Crescimento , Humanos , Injeções Subcutâneas , Masculino , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/efeitos adversos , Peptídeo Natriurético Tipo C/uso terapêuticoRESUMO
The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.
Assuntos
Aorta/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Natriuréticos/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Animais , Aorta/metabolismo , Pressão Sanguínea , Citocinas/metabolismo , Glutationa/metabolismo , Rim/efeitos dos fármacos , Masculino , Natriuréticos/administração & dosagem , Natriuréticos/uso terapêutico , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/uso terapêutico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Superóxidos/metabolismo , VasoconstriçãoRESUMO
C-type natriuretic peptide (CNP)-knockout (KO) rats exhibit impaired skeletal growth, with long bones shorter than those in wild-type (WT) rats. This study compared craniofacial morphology in the CNP-KO rat with that in the Spontaneous Dwarf Rat (SDR), a growth hormone (GH)-deficient model. The effects of subcutaneous administration of human CNP with 53 amino acids (CNP-53) from 5 weeks of age for 4 weeks on craniofacial morphology in CNP-KO rats were also investigated. Skulls of CNP-KO rats at 9 weeks of age were longitudinally shorter and the foramen magnum was smaller than WT rats. There were no differences in foramen magnum stenosis and midface hypoplasia between CNP-KO rats at 9 and 33 weeks of age. These morphological features were the same as those observed in CNP-KO mice and activated fibroblast growth factor receptor 3 achondroplasia-phenotype mice. In contrast, SDR did not exhibit foramen magnum stenosis and midface hypoplasia, despite shorter stature than in control rats. After administration of exogenous CNP-53, the longitudinal skull length and foramen magnum size in CNP-KO rats were significantly greater, and full or partial rescue was confirmed. The synchondrosis at the cranial base in CNP-KO rats is closed at 9 weeks, but not at 4 weeks of age. In contrast, synchondrosis closure in CNP-KO rats treated with CNP-53 was incomplete at 9 weeks of age. Administration of exogenous CNP-53 accelerated craniofacial skeletogenesis, leading to improvement in craniofacial morphology. As these findings in CNP-KO rats are similar to those in patients with achondroplasia, treatment with CNP-53 or a CNP analog may be able to restore craniofacial morphology and foramen magnum size as well as short stature.
Assuntos
Constrição Patológica , Face/anormalidades , Forame Magno/patologia , Peptídeo Natriurético Tipo C/deficiência , Peptídeo Natriurético Tipo C/uso terapêutico , Acondroplasia/tratamento farmacológico , Animais , Desenvolvimento Ósseo , Humanos , Ratos , Fatores de TempoRESUMO
Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2cC342Y/+ and Fgfr2c+/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.
Assuntos
Disostose Craniofacial/tratamento farmacológico , Craniossinostoses/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Animais , Animais Recém-Nascidos , Disostose Craniofacial/genética , Disostose Craniofacial/patologia , Craniossinostoses/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Peptídeo Natriurético Tipo C/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. RECENT FINDINGS: The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.
Assuntos
Osteocondrodisplasias/diagnóstico , Acondroplasia/diagnóstico , Acondroplasia/diagnóstico por imagem , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Fosfatase Alcalina/uso terapêutico , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/tratamento farmacológico , Doenças do Desenvolvimento Ósseo/genética , Terapia de Reposição de Enzimas , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/diagnóstico por imagem , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/genética , Imunoglobulina G/uso terapêutico , Natriuréticos/uso terapêutico , Peptídeo Natriurético Tipo C/uso terapêutico , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/tratamento farmacológico , Osteocondrodisplasias/genética , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Radiografia , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes , Análise de Sequência de DNA , Proteína de Homoeobox de Baixa Estatura/deficiência , Proteína de Homoeobox de Baixa Estatura/genéticaRESUMO
Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia.
Assuntos
Androgênios/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Natriuréticos/uso terapêutico , Peptídeo Natriurético Tipo C/uso terapêutico , Acondroplasia/tratamento farmacológico , Nanismo Hipofisário/tratamento farmacológico , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Oxandrolona/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Proteínas Recombinantes , Testosterona/uso terapêutico , Síndrome de Turner/tratamento farmacológicoRESUMO
Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH.
Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Neprilisina/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/genética , Acondroplasia/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Macaca fascicularis , Masculino , Camundongos , Células NIH 3T3 , Peptídeo Natriurético Tipo C/metabolismo , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Tipo C/uso terapêutico , Ratos , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: C-type natriuretic peptide (CNP), secreted by vascular endothelial cells, belongs to a family of peptides that includes atrial and brain natriuretic peptides. CNP exhibits many vasoprotective effects against pulmonary hypertension and pulmonary fibrosis. The objective of this study was to investigate the prophylactic effects of CNP in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: C57BL/6 mice were divided into three groups as follows: normal control mice (n = 13), LPS mice treated with vehicle (n = 12), and LPS mice treated with CNP (n = 12). Twenty-four hours after tail vein injection of LPS, histopathologic, gene expression, and bronchoalveolar lavage fluid (BALF) assessments were performed on the lungs. To examine the neutrophils in the lungs, cells positive for myeloperoxidase staining were detected by immunohistochemistry. BALF cytokine levels were analyzed by enzyme-linked immunosorbent assays. Gene expression in lung tissue was analyzed by real-time polymerase chain reaction. RESULTS: CNP significantly attenuated the elevation of leukocyte cell counts and levels of tumor necrosis factor-alpha, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine in the BALF after LPS injection. Furthermore, there were significantly fewer myeloperoxidase-positive cells in lungs treated with CNP after LPS injection. In lungs of CNP-treated mice, expression of the monocyte chemoattractant protein-1, S100A8, and E-selectin genes was significantly lower than that in vehicle-treated mice. CONCLUSIONS: CNP had a protective effect on ALI induced by LPS by reducing inflammatory cell infiltration. CNP may hold promise in therapeutic strategies for ALI after pulmonary resection surgery.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Peptídeo Natriurético Tipo C/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Calgranulina A/metabolismo , Quimiocina CCL2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Selectina E/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Peptídeo Natriurético Tipo C/farmacologiaRESUMO
Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia.
Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Modelos Animais de Doenças , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/patologia , Humanos , Camundongos , Mutação , Peptídeo Natriurético Tipo C/química , Peptídeo Natriurético Tipo C/fisiologia , Peptídeo Natriurético Tipo C/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Radiografia , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/patologia , Resultado do TratamentoRESUMO
Natriuretic peptides elicit vasodilation, increased sodium excretion and concomitant diuresis, and counteract the RAAS. In the heart itself, natriuretic peptides may also act anti-inflammatory and antifibrotic. This has led to the pursuit of natriuretic peptides and chemically modified peptides as adjunctive therapy in myocardial ischaemia. However, natriuretic peptide infusion may also influence the endogenous natriuretic peptide response and lipid accumulation. We hypothesised that a) natriuretic peptide infusion (BNP and CD-NP) is cardiomyocyte protective, b) affects the endogenous response, and c) facilitate cardiac lipid accumulation. We examined these effects in a minimally invasive porcine model of regional cardiac ischaemia and reperfusion. The studies were supplemented by a 48-hour porcine model of ischemia and reperfusion as well as an in vitro study of BNP administered in a HL-1 cell model of "ischaemia/reperfusion". Infarct size was determined by TTC staining, plasma troponin T release, and total RNA integrity in cardiac tissue samples. The endogenous response was assessed by a processing-independent proANP immunoassay and mRNA quantitation. Lipids in plasma and myocardial tissue were determined by TLC. The studies show that natriuretic peptides decrease cardiomyocyte damage, possibly partly through indirect mechanisms. Furthermore, BNP infusion completely inverts the endogenous response, whereas CD-NP infusion does not. Finally, both natriuretic peptides increase plasma free fatty acids, which is associated with an increased cardiac lipid accumulation in non-ischaemic myocardium. In conclusion, the studies suggest that natriuretic peptides are beneficial in terms of reduced cardiac injury. In addition, the endogenous natriuretic peptide response is inverted. The results advocate for pursuing natriuretic peptide treatment in ischaemia/reperfusion damage. However, the metabolic consequences in a cardiac tissue challenged by ischaemia should be pursued before testing the peptides in patients.