The Natural History of Autosomal Dominant Osteopetrosis Type 2

2 型常染色体显性骨石症的自然史

基本信息

批准号：
10218062
负责人：
Michael J Econs
金额：
$ 20.62万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-16 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218062
关键词：
Adult Affect Age Albers-Schonberg disease Alleles Animal Model Appearance Biochemical Biological Biological Markers Biometry Blindness Bone Density Bone Diseases Bone Resorption Bone necrosis Cell Culture Techniques Chloride Channels Clinical Clinical Trials Clinical Trials Design Data Diagnostic radiologic examination Disease Disease Marker Disease Outcome Disease Progression Dominant-Negative Mutation Endocrinology Family Fracture Functional disorder Future Genes Genotype Goals Grant Human Impairment Individual Interferon gamma 1b Internal Medicine Jaw Laboratories Life Longterm Follow-up Maxilla Measurement Measures Missense Mutation Modeling Morbidity - disease rate Mus Mutation National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural History Observational Study Osteoclasts Osteomyelitis Outcome Pain Pancytopenia Participant Patient Outcomes Assessments Patient-Focused Outcomes Patients Pediatrics Penetrance Personal Communication Pharmacologic Substance Phenotype Physical therapy Quality of life Radiology Specialty Rare Diseases Registries Research Research Personnel Risk Factors Sampling Severities Severity of illness Source Surveys Testing Therapeutic Clinical Trial Therapeutic Effect Time Translating United States National Institutes of Health Variant base bone clinically relevant cohort data repository design disability early childhood effective therapy hematopoietic cell transplantation in vivo individual patient kindred knock-down meetings member mouse model multidisciplinary mutant novel marker novel therapeutic intervention novel therapeutics patient registry population based preclinical study programs prospective recruit

项目摘要

Abstract NIAMS Natural Hx Proposal Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare osteosclerotic disorder resulting from impaired osteoclastic bone resorption due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies widely. Affected individuals typically have at least one significant clinical manifestation including fractures, osteonecrosis, osteomyelitis, blindness, or bone marrow failure. Ten of our patients have died (out of >80 with clinical manifestations) either of disease manifestations or from attempts at therapy for severe disease. The natural progression of disease manifestations in ADO2 is unknown, although limited data suggests that the disease gets worse with age. Although no effective therapy is currently available, studies in animal models have generated promising data and human trials on are on the horizon. Therefore, it is imperative to understand the natural history of ADO2, including reliable biological markers and relevant patient centered outcomes, to measure therapeutic effect, and to guide the design of clinical trials. The proposed natural history study will establish a cohort of serially phenotyped subjects to capture clinically important outcomes and characterize variations in disease severity, progression of disease, and novel biomarkers for current or future disease severity. The goals of this study are to 1) identify clinically relevant biological (clinical, biochemical, densitometric, or radiographic) and patient-reported outcomes and 2) determine the natural history of ADO2, including the rate of disease progression. We will focus on the following specific aims: Specific Aim 1: Determine key markers of disease severity and endpoints for a clinical trial. A. Refine and validate a composite clinical severity grading scale. A. Combine samples and measurements from our prior studies with prospectice serial measurements in participating subjects to determine which clinical, biological, radiological, and densitometric endpoints best define current disease severity and predict future disease severity and outcomes. B. Test the hypothesis that ADO2 disease severity gets worse with age. C. Compare measures obtained in the studies outlined above in patients with the 3 most common mutations in our kindreds (G215R, R286W, and R767W) to identify genotype-phenotype correlations, and whether the individual mutations predict disease severity. Specific Aim 2: Establish an electronic ADO2 patient registry, which will collect population-based, longitudinal quality-of-life, pain, disability and other survey-based data from any individual with osteopetrosis. This registry will serve as a data repository for subjects participating in the research aims above, will provide long-term follow-up data continuing beyond the completion of this grant, and be an ongoing source of potential recruitment to future clinical trials of novel therapies.

摘要 NIAMS Natural Hx 提案抽象的常染色体显性骨硬化症 2 型 (ADO2) 是一种罕见的骨硬化性疾病，由骨质疏松引起由于氯通道 7 基因突变导致破骨细胞骨吸收，该基因通过以下方式引起疾病：显性负机制。外显率约为 66%，疾病严重程度差异很大。做作的个体通常具有至少一种显着的临床表现，包括骨折、骨坏死、骨髓炎、失明或骨髓衰竭。我们的 10 名患者已死亡（超过 80 名临床患者已死亡）表现）要么是疾病表现，要么是尝试治疗严重疾病。自然的 ADO2 疾病表现的进展尚不清楚，尽管有限的数据表明该疾病随着年龄的增长会变得更糟。尽管目前尚无有效的治疗方法，但动物模型研究表明产生了有希望的数据，人体试验即将进行。因此，有必要了解 ADO2 的自然史，包括可靠的生物标志物和相关的以患者为中心的结果，衡量治疗效果，并指导临床试验的设计。拟议的自然历史研究将建立一系列连续表型受试者，以捕获临床重要结果并表征疾病严重程度、疾病进展以及当前或未来疾病的新生物标志物的变化严重程度。本研究的目标是 1) 确定临床相关的生物学（临床、生化、密度测定或放射照相）和患者报告的结果，2）确定 ADO2 的自然史，包括疾病进展的速度。我们将重点关注以下具体目标：具体目标 1：确定疾病严重程度的关键标志物和临床试验的终点。 A. 完善并验证复合临床严重程度分级量表。 A. 将我们之前研究的样本和测量值与前景系列测量值相结合参与受试者确定哪些临床、生物学、放射学和光密度终点最好定义当前疾病的严重程度并预测未来疾病的严重程度和结果。 B. 检验 ADO2 疾病严重程度随着年龄增长而恶化的假设。 C. 比较上述研究中针对具有 3 种最常见突变的患者获得的测量结果在我们的亲属（G215R、R286W 和 R767W）中鉴定基因型-表型相关性，以及是否个体突变可预测疾病的严重程度。具体目标 2：建立电子 ADO2 患者登记系统，该登记系统将收集基于人群的纵向数据来自任何石骨病患者的生活质量、疼痛、残疾和其他基于调查的数据。这个注册表将作为参与上述研究目标的受试者的数据存储库，将提供长期后续数据在本次赠款完成后继续存在，并成为潜在的持续来源招募新疗法的未来临床试验。