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

基本信息

批准号：
10700164
负责人：
Rebecca Clare Ahrens-Nicklas
金额：
$ 25.75万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/10700164
关键词：
Adaptive Behaviors Address Advocacy Age Aspartylglucosaminuria Attenuated Biochemical Markers Biological Assay Biological Markers Biological Specimen Banks Cells Cessation of life Child Childhood Chondrodysplasia Punctata Chondroitin Classification Clinical Clinical Trials Clinical Trials Design Clinical stratification Collection Data Data Analyses Data Set Deficiency Diseases Degenerative Disorder Development Disease Disease Marker Disease Progression Disease stratification 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 biobank biomarker validation burden of illness clinically relevant cohort combinatorial comparison control 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

项目摘要

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.

项目摘要多硫酸酶缺乏症（MSD）是一种超稀有的，多型系统的，进行性神经退行性的紊乱。死亡时的中位年龄为13岁，没有批准的疾病修饰疗法。 MSD 由SUMF1中的致病变异引起，该变体编码了甲基甘氨酸产生酶（FGE）。由于FGE对所有硫酸酶的必要激活，MSD患者患有硫酸酶活性降低的组合作用。这些硫酸酶中的一些与良好有关描述的是单基因疾病，包括5种亚型粘多糖（MPS）和过时的疾病白细胞营养不良（MLD）。总体而言，MSD的体征和症状是渐进的，尽管具体功能可能是可变的。尽管在临床前模型中有积极发展治疗选择，但缺乏强大的，MSD进展和严重程度的定量标记。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 MSD的疾病严重程度。有几种活跃的临床前研究计划致力于开发新型MSD 治疗。基于AAV9的基因疗法改善了疾病的生化标志物，并延长了生存 MSD的鼠标模型。为了准备将来的临床试验，我们已将30多名患者招募到我们的 MSD自然史研究和生物库。我们对该数据集的初步分析揭示了关键表型功能，例如运动和喂养技能的丧失，似乎与疾病进展和基因型。在本提案的目标1中，我们将基于先前的工作来发展定量结果捕获MSD中有意义的临床症状进展的测量。我们将在我们的回顾性MSD队列并前瞻性验证它。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。通过对临床记录的分析，我们发现患者可以分为严重和减弱基于取得的行走的亚组。虽然这对回顾性分析很有帮助，但确定通常是婴儿的新诊断患者可能很难分类。没有建立的生物标志物可以区分MSD亚组。在AIM 2中，我们将调查非还原糖胺聚糖（gag-nres）的最终物种，在MSD中积聚的独特寡糖，与疾病的严重程度相关。在许多相关MPS中，GAG-NRES是验证良好的生物标志物疾病。我们预计MSD患者将升高总体GAG-NRE物种，并且升高的大小将与临床严重程度成正比。总体而言，MSD疾病量表和在我们准备移动有希望的时候，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了人类的第一次试验。