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JCI Insight Nov 2023Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including...
Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.
Topics: Mice; Humans; Animals; Receptor, Fibroblast Growth Factor, Type 3; Porphyrins; Achondroplasia; Signal Transduction; Neoplasms
PubMed: 37824212
DOI: 10.1172/jci.insight.171257 -
Endocrine Journal Apr 2024Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the...
Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.
PubMed: 38569854
DOI: 10.1507/endocrj.EJ24-0109 -
PloS One 2023Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for...
Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.
Topics: Mice; Animals; Meclizine; Drug Repositioning; Achondroplasia; Area Under Curve; Bone Development
PubMed: 37428729
DOI: 10.1371/journal.pone.0283425 -
Nature Reviews. Endocrinology May 2024
PubMed: 38740894
DOI: 10.1038/s41574-024-00994-w -
EClinicalMedicine Nov 2023TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing....
Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.
BACKGROUND
TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.
METHODS
ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).
FINDINGS
Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.
INTERPRETATION
This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.
FUNDING
Ascendis Pharma, A/S.
PubMed: 37823031
DOI: 10.1016/j.eclinm.2023.102258 -
The Journal of Clinical Endocrinology... Apr 2024Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing...
Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.
Topics: Child; Humans; Endocrinologists; Osteochondrodysplasias; Achondroplasia; Prader-Willi Syndrome
PubMed: 38078681
DOI: 10.1210/clinem/dgad726 -
Journal of Endocrinological... Feb 2024This study aimed to assess the real-world management of achondroplasia in Italy.
PURPOSE
This study aimed to assess the real-world management of achondroplasia in Italy.
METHODS
Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery.
RESULTS
In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2-5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians' reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers.
CONCLUSION
This survey provides insight into the real-world management of individuals with achondroplasia in Italy.
Topics: Child; Humans; Child, Preschool; Quality of Life; Caregivers; Achondroplasia; Surveys and Questionnaires; Parents
PubMed: 37466810
DOI: 10.1007/s40618-023-02151-y -
Genetics in Medicine : Official Journal... Oct 2023Skeletal dysplasia are heterogeneous conditions affecting the skeleton. Common nutrition issues include feeding difficulties, obesity, and metabolic complications. This...
PURPOSE
Skeletal dysplasia are heterogeneous conditions affecting the skeleton. Common nutrition issues include feeding difficulties, obesity, and metabolic complications. This systematic scoping review aimed to identify key nutrition issues, management strategies, and gaps in knowledge regarding nutrition in skeletal dysplasia.
METHODS
The databases Ovid MEDLINE, Ovid EMBASE, Ebsco CINAHL, Scopus, and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews were searched. Reference lists and citing literature for included studies were searched. Eligible studies included participants with skeletal dysplasia and described: anthropometry, body composition, nutrition-related biochemistry, clinical issues, dietary intake, measured energy or nutrition requirements, or nutrition interventions.
RESULTS
The literature search identified 8509 references from which 138 studies were included (130 observational, 3 intervention, 2 systematic reviews, and 3 clinical guidelines). Across 17 diagnoses identified, most studies described osteogenesis imperfecta (n = 50) and achondroplasia or hypochondroplasia (n = 47). Nutrition-related clinical issues, biochemistry, obesity, and metabolic complications were most commonly reported, and few studies measured energy requirements (n = 5).
CONCLUSION
Nutrition-related comorbidities are documented in skeletal dysplasia; yet, evidence to guide management is scarce. Evidence describing nutrition in rarer skeletal dysplasia conditions is lacking. Advances in skeletal dysplasia nutrition knowledge is needed to optimize broader health outcomes.
Topics: Humans; Comorbidity; Dwarfism; Obesity; Osteochondrodysplasias; Systematic Reviews as Topic
PubMed: 37330695
DOI: 10.1016/j.gim.2023.100920 -
Obesity Surgery May 2024Achondroplasia is a common skeletal dysplasia with a high prevalence of obesity in adulthood. Bariatric surgery has been shown to be effective in treating obesity and...
BACKGROUND
Achondroplasia is a common skeletal dysplasia with a high prevalence of obesity in adulthood. Bariatric surgery has been shown to be effective in treating obesity and related comorbidities, but its feasibility and effectiveness in patients with achondroplasia have not been clearly established.
OBJECTIVES
The objective of this study was to evaluate the feasibility and effectiveness of bariatric surgery in patients with achondroplasia.
SETTING
This study was performed in France, and bariatric surgeons from the Société Française et Francophone de Chirurgie de l'Obésité et des Maladies Métaboliques (French Francophone Society of Surgery for Obesity or Metabolic Diseases) were asked to participate.
METHODS
Two adult women with confirmed achondroplasia and a high BMI were selected for laparoscopic sleeve gastrectomy. Preoperative data were collected, including demographic information, comorbidities, and follow-up at 1, 3, and 6 months and 1 year after surgery. Complications were monitored and recorded.
RESULTS
Both patients had good excess weight loss outcomes, with an average excess weight loss of 60.5% 1 year after surgery. One patient had a follow-up of 3 years and an excess weight loss of 44%. The surgery was well-tolerated, and no major complications were observed.
CONCLUSIONS
Bariatric surgery is feasible and effective in patients with achondroplasia, with good outcomes for excess weight loss and related comorbidities. These findings suggest that bariatric surgery should be considered a treatment option for patients with achondroplasia and obesity.
Topics: Adult; Humans; Female; Obesity, Morbid; Feasibility Studies; Retrospective Studies; Bariatric Surgery; Obesity; Gastrectomy; Weight Loss; Achondroplasia; Laparoscopy; Treatment Outcome
PubMed: 38564174
DOI: 10.1007/s11695-024-07144-1 -
Biomolecules Jan 2024Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread... (Review)
Review
Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread clinical use for any condition. Notably, many drugs currently on the market, including the first analgesic aspirin, are derived from plant extracts, emphasizing the historical significance of natural products in drug development. Curcumin and resveratrol, well-studied nutraceuticals, have excellent safety profiles with relatively mild side effects. Their long history of safe use and the natural origins of numerous drugs contrast with the unfavorable reputation associated with nutraceuticals. This review aims to explore the nutraceutical potential for treating pseudoachondroplasia, a rare dwarfing condition, by relating the mechanisms of action of curcumin and resveratrol to molecular pathology. Specifically, we will examine the curcumin and resveratrol mechanisms of action related to endoplasmic reticulum stress, inflammation, oxidative stress, cartilage health, and pain. Additionally, the barriers to the effective use of nutraceuticals will be discussed. These challenges include poor bioavailability, variations in content and purity that lead to inconsistent results in clinical trials, as well as prevailing perceptions among both the public and medical professionals. Addressing these hurdles is crucial to realizing the full therapeutic potential of nutraceuticals in the context of pseudoachondroplasia and other health conditions that might benefit.
Topics: Curcumin; Resveratrol; Dietary Supplements; Biological Products; Achondroplasia
PubMed: 38397390
DOI: 10.3390/biom14020154