Disease Severity Stratification in Multiple Sulfatase Deficiency

多种硫酸酯酶缺乏症的疾病严重程度分层

• 批准号: 10513906
• 负责人: Rebecca Clare Ahrens-Nicklas
• 金额: $ 23.25万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513906
• 关键词: Adaptive Behaviors; Address; Advocacy; Age; Aspartylglucosaminuria; Attenuated; Biochemical Markers; Biological Assay; Biological Markers; Biological Specimen Banks; Cell Therapy; Cessation of life; Child; Childhood; Chondrodysplasia Punctata; Chondroitin; Classification; Clinical; Clinical Trials; Clinical Trials Design; Collection; Data; Data Set; Deficiency Diseases; Degenerative Disorder; Development; Disease; Disease Marker; Disease Progression; Disorder of neurometabolic regulation; Elements; Enrollment; Enzymes; Exclusion Criteria; Exhibits; FDA approved; Fatigue; Floor; Foundations; Funding; Future; GAG Gene; Genotype; Glycosaminoglycans; Heparitin Sulfate; Human; Individual; Infant; Laboratories; Letters; Measurement; Measures; Mediating; Medical Records; Mendelian disorder; Metachromatic Leukodystrophy; Motor; Mucopolysaccharidoses; Mucopolysaccharidosis II; Natural History; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Newly Diagnosed; Oligosaccharides; Outcome; Outcome Measure; Pathogenicity; Patients; Performance; Phenotype; Pilot Projects; Population; Population Control; Pre-Clinical Model; Prospective Studies; Protocols documentation; Records; Reporting; Research; Retrospective cohort; Sampling; Severities; Severity of illness; Signs and Symptoms; Stratification; Subgroup; Sulfatases; Symptoms; Testing; Therapeutic; Urine; Validation; Variant; Work; X-Linked Ichthyosis; base; biobank; burden of illness; case control; clinically relevant; cohort; combinatorial; design; effective therapy; enzyme activity; experience; feeding; first-in-human; formylglycine; functional outcomes; gene therapy; improved; innovation; mouse model; novel; novel marker; patient stratification; pre-clinical; pre-clinical research; programs; prospective; skills; small molecule; specific biomarkers; theories; therapeutic development; tool

PROJECT SUMMARY Multiple sulfatase deficiency (MSD) is an ultra-rare, multi-systemic, progressive neurodegenerative disorder. Median age at death is 13 years, and there are no approved disease modifying therapies. MSD arises from pathogenic variants in SUMF1, which encodes the formylglycine generating enzyme (FGE). Because of the necessary activation of all sulfatases by FGE, patients with MSD suffer from the combinatorial effect of decreased sulfatase activity. Some of these sulfatases are associated with well- described monogenic disorders including 5 subtypes of mucopolysaccharidosis (MPS) and metachromatic leukodystrophy (MLD). Overall, the signs and symptoms of MSD are progressive, although the specific features can be variable. Despite the active development of therapeutic options in preclinical models, robust, quantitative markers of MSD progression and severity are lacking. We hypothesize that a disease-specific scale and novel glycosaminoglycan biomarkers will capture symptom burden and disease severity in MSD. There are several active preclinical research programs focused on developing novel MSD treatments. AAV9-based gene therapy improves biochemical markers of disease and prolongs survival in mouse models of MSD. To prepare for future clinical trials, we have enrolled more than 30 patients into our MSD natural history study and biobank. Our preliminary analysis of this dataset revealed key phenotypic features, such as loss of motor and feeding skills, that appear to correlate with disease progression and genotype. In Aim 1 of this proposal, we will build upon our prior work to develop a quantitative outcome measure that captures meaningful clinical symptom progression in MSD. We will iteratively test this tool in our retrospective MSD cohort and validate it prospectively. We plan to use this novel MSD scale to measure longitudinal change, stratify patients, and determine inclusion/exclusion criteria in upcoming clinical trials. Through analysis of clinical records, we found that patients can be divided into severe and attenuated subgroups based on attainment of ambulation. While this is helpful with retrospective analysis, determining subject classification may be difficult in newly-diagnosed patients, who are often infants. There is no established biomarker that can differentiate MSD subgroups. In Aim 2, we will investigate if the nonreducing end species of glycosaminoglycans (GAG-NREs), unique oligosaccharides that accumulate in MSD, correlate with disease severity. GAG-NREs are well-validated biomarkers in a number of related MPS disorders. We anticipate that overall GAG-NRE species will be elevated in MSD patients, and that the magnitude of elevation will be proportional to clinical severity. Collectively, the MSD disease scale and biomarkers developed here will be essential to clinical trial design as we prepare to move promising preclinical programs into first-in-human trials.

项目概要 多种硫酸酯酶缺乏症 (MSD) 是一种极其罕见的、多系统的、进行性神经退行性疾病 紊乱。死亡中位年龄为 13 岁，目前尚无获批的疾病修饰疗法。默沙东 源自 SUMF1 的致病性变异，SUMF1 编码甲酰甘氨酸生成酶 (FGE)。 由于 FGE 必须激活所有硫酸酯酶，因此 MSD 患者会遭受 硫酸酯酶活性降低的组合效应。其中一些硫酸酯酶与良好的 描述了单基因疾病，包括 5 种粘多糖贮积症 (MPS) 和异染性亚型 脑白质营养不良（MLD）。总体而言，MSD 的体征和症状是进行性的，尽管具体情况如下： 特征可以是可变的。尽管临床前模型中的治疗方案正在积极开发， 缺乏强有力的、定量的 MSD 进展和严重程度标记。我们假设一个 疾病特异性量表和新型糖胺聚糖生物标志物将捕获症状负担并 MSD 中疾病的严重程度。 有几个活跃的临床前研究项目专注于开发新型 MSD 治疗。基于 AAV9 的基因治疗可改善疾病的生化标志物并延长患者的生存期 MSD小鼠模型。为了为未来的临床试验做准备，我们已经招募了 30 多名患者。 默沙东自然历史研究和生物样本库。我们对该数据集的初步分析揭示了关键表型 一些特征，例如运动和进食技能的丧失，似乎与疾病进展和 基因型。在本提案的目标 1 中，我们将在之前的工作基础上制定量化成果 捕获 MSD 有意义的临床症状进展的测量方法。我们将在我们的项目中迭代测试这个工具 回顾性 MSD 队列并进行前瞻性验证。我们计划使用这种新颖的 MSD 量表来测量 纵向变化，对患者进行分层，并确定即将进行的临床试验中的纳入/排除标准。 通过临床记录分析，我们发现患者可分为重症和减毒 基于行走能力的亚组。虽然这有助于回顾性分析，但确定 对于新诊断的患者（通常是婴儿）来说，主题分类可能很困难。没有 建立了可以区分 MSD 亚组的生物标志物。在目标 2 中，我们将研究非还原性是否 糖胺聚糖 (GAG-NRE) 的最终种类，是在 MSD 中积累的独特寡糖， 与疾病严重程度相关。 GAG-NRE 是许多相关 MPS 中经过充分验证的生物标志物 失调。我们预计 MSD 患者中总体 GAG-NRE 种类将会升高，并且 升高的幅度与临床严重程度成正比。总的来说，MSD 疾病量表和 当我们准备迈向有前途的阶段时，这里开发的生物标志物对于临床试验设计至关重要 临床前计划进入首次人体试验。