Non-invasive functional assessment and pathogenesis of Morquio A

Morquio A 的无创功能评估和发病机制

基本信息

批准号：
10398200
负责人：
Shunji Tomatsu
金额：
$ 59.35万
依托单位：
ALFRED I. DU PONT HOSP FOR CHILDREN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398200
关键词：
Acetylgalactosamine Activities of Daily Living Age Angiography Awareness Biochemical Biochemical Markers Biological Markers Birth Bone Density Bone Diseases Cardiopulmonary Cartilage Cervical Characteristics Chondroitin Sulfate C Clinic Clinical Clinical Treatment Clinical Trials Clinical assessments Collaborations Communities Consumption Data Databases Development Diagnosis Disease Disease Progression Distal Dwarfism Dysplasia Effectiveness Enrollment Enzymes Equipment Evaluation Femur Foundations Future Gait Galanin Glycosaminoglycan Degradation Pathway Glycosaminoglycans Goals Growth Health Hearing Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hip region structure Home Institution Interdisciplinary Study Intervention Joint Laxity Joints Keratan Sulfate Kyphosis deformity of spine Lateral Lead Lesion Life Lung Lung Capacity Magnetic Resonance Imaging Measurement Measures Medical Methods Monitor Motivation Mucopolysaccharidoses Mucopolysaccharidosis IV A Natural History Obstruction Operative Surgical Procedures Orthopedic Surgery Osteotomy Outcome Outcome Measure Pathogenesis Patient Care Patients Pattern Pharmacologic Substance Phenotype Physical assessment Physicians Physiologic Ossification Physiologic calcification Placebo Effect Postoperative Period Prognostic Marker Publications Pulmonary function tests Questionnaires Recording of previous events Records Registries Research Research Personnel Research Proposals Respiratory Function Tests Science Severities Severity of illness Site Specialist Specimen Stenosis Sulfatases Sulfate Surrogate Markers System Testing Therapeutic Therapeutic Intervention Time Training Treatment Efficacy Treatment outcome Visit Walking Wheelchairs base bone clinical candidate clinical efficacy clinical practice clinical research site clinically relevant compliance behavior enzyme replacement therapy exhaust experience functional status gait examination gene therapy innovation interest medical attention patient mobility patient population pediatric patients physically handicapped potential biomarker predictive marker prognostic programs pulmonary function reconstruction research clinical testing response risk stratification skeletal skeletal abnormality skeletal disorder skeletal dysplasia skeletal muscle weakness stem cell therapy therapy development treatment response

项目摘要

7. Project Summary/Abstract Mucopolysaccharidosis IVA (MPS IVA, Morquio A Disease) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulfate sulfatase (GALNS). GALNS catalyzes the degradation of the glycosaminoglycans: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). MPS IVA patients develop a characteristic skeletal dysplasia due to the progressive storage of KS and C6S. Patients appear healthy at birth, although some patients present with abnormal skeletal dysplasia even at birth. Patients usually come to medical attention within two years of life because of short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, genu valgum, or hypermobile joints. Patients with severe phenotype often do not survive beyond a few decades of life because of cervical instability/stenosis, tracheal obstruction, and cardiopulmonary compromise. Patients require multiple orthopedic surgeries (cervical decompression/fusion, osteotomy, hip reconstruction and replacement, etc.) throughout their lifetime. Enzyme replacement therapy and hematopoietic stem cell therapy are available clinically. Gene therapy and enzyme degradation substrate therapy are under development. In 1998, we began collecting medical information from patients in the Registry Database. The database contains around 400 patients and has established a growth chart that indicates marked poor growth with the imbalance and consequent poor health in MPS IVA. However, since these data are based on responses to a self-completion questionnaire, there are inherent limitations to the data and their interpretation. Current clinical assessments of therapies for MPS IVA patients are a 6-min walk test, a 3-min stair climb test, and forced pulmonary function test. These endurance tests are difficult for small children, patients in wheelchairs, and patients undergoing surgical procedures. Methods used to assess skeletal dysplasia disorders can be expensive, time-consuming, and exhausting for the patients. Better methods for assessment, including in-home evaluations, are needed to evaluate clinical efficacy and to provide optimal clinical treatments for MPS IVA patients. The proposed project will assess multiple domains non-invasively, which includes pulmonary function, bone mineralization, gait pattern, laxity of joints, tracheal function, and hearing function. Proposed non-invasive assessments will provide an effective and innovative way of characterizing the disease and evaluating the benefits of therapies even in small but diverse patient populations despite age and physical handicaps. Over 100 MPS IVA patients have been enrolled in our clinic, making our institution the most popular site in the world and ideally suited to complete this project. The assessment program with non-invasive methods will have a significant impact on science and health by detailing the progression and pathogenesis of major skeletal problems in MPS IVA. The outcome of this project will also define clinical endpoints to measure the efficacy of future clinical products and interventions and may apply to other skeletal dysplasias. 1

7. 项目总结/摘要粘多糖贮积症 IVA（MPS IVA，Morquio A 病）是一种罕见的常染色体隐性遗传病，由溶酶体酶 N-乙酰半乳糖胺 6-硫酸酯硫酸酯酶 (GALNS) 缺乏。 GALNS 催化糖胺聚糖的降解：硫酸角质素 (KS) 和 6-硫酸软骨素 (C6S)。 MPS IVA 由于 KS 和 C6S 的逐渐储存，患者出现特征性骨骼发育不良。患者尽管有些患者在出生时就出现异常骨骼发育不良，但出生时看起来很健康。患者通常在出生后两年内因躯干短小侏儒症、齿状突发育不全、鸡胸、脊柱后凸、膝外翻或关节过度活动。具有严重表型的患者通常不由于颈椎不稳定/狭窄、气管阻塞和心肺损害。患者需要多次骨科手术（宫颈减压/融合、截骨术、髋关节重建和置换等）贯穿其一生。酶替代疗法造血干细胞治疗已进入临床。基因治疗和酶降解底物疗法正在开发中。 1998 年，我们开始在登记处收集患者的医疗信息数据库。该数据库包含约 400 名患者，并建立了生长图表来表明 MPS IVA 的不平衡和随之而来的健康状况不佳导致生长缓慢。然而，由于这些数据基于对自我完成调查问卷的答复，数据及其本身存在固有的局限性解释。目前对 MPS IVA 患者治疗的临床评估是 6 分钟步行测试、3 分钟步行测试爬楼梯测试、强制肺功能测试。这些耐力测试对于小孩子来说很难，坐轮椅的患者以及接受外科手术的患者。用于评估骨骼的方法发育不良疾病对于患者来说可能是昂贵、耗时且疲惫的。更好的方法需要进行评估，包括家庭评估，以评估临床疗效并提供最佳的治疗方案 MPS IVA 患者的临床治疗。拟议的项目将以非侵入性方式评估多个领域，其中包括肺功能、骨矿化、步态模式、关节松弛度、气管功能和听觉功能。拟议的非侵入性评估将提供一种有效且创新的方法即使在规模较小但多样化的患者中，也能表征疾病并评估治疗的益处尽管年龄和身体有缺陷，但人口。我们诊所已招收超过 100 名 MPS IVA 患者，使我们的机构成为世界上最受欢迎的网站，并且非常适合完成该项目。这采用非侵入性方法的评估计划将对科学和健康产生重大影响详细介绍了 MPS IVA 中主要骨骼问题的进展和发病机制。该项目的成果还将定义临床终点来衡量未来临床产品和干预措施的功效，并可能适用于其他骨骼发育不良。 1