Disease Severity Stratification in Multiple Sulfatase Deficiency

项目摘要 多发性硫酸酯酶缺乏症（MSD）是一种非常罕见的，多系统的，进行性神经退行性疾病， disorder.死亡时的中位年龄为13岁，并且没有批准的疾病改善疗法。MSD 由SUMF 1的致病性变体引起，SUMF 1编码甲酰甘氨酸生成酶（FGE）。 由于FGE对所有硫酸酯酶的必要激活，患有MSD的患者遭受了FGE的严重损害。 硫酸酯酶活性降低的组合效应。其中一些硫酸酯酶与- 描述了单基因疾病，包括粘多糖样沉积症（MPS）和异染性 脑白质营养不良（MLD）。总的来说，MSD的体征和症状是渐进的，尽管特定的 特征可以是可变的。尽管在临床前模型中积极开发了治疗选择， 缺乏可靠的、定量的MSD进展和严重程度的标志物。我们假设 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， 在MSD中的疾病严重程度。 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AAV 9的基因治疗改善了疾病的生化标志物和患者的存活率。 MSD的小鼠模型。为了准备未来的临床试验，我们已经招募了30多名患者参加我们的 MSD自然历史研究和生物库。我们对该数据集的初步分析显示， 特征，如运动和进食技能的丧失，似乎与疾病进展相关， 基因型在本提案的目标1中，我们将在先前工作的基础上制定量化成果 这是一项能够捕捉MSD中有意义的临床症状进展的指标。我们将在我们的 回顾性MSD队列研究并进行前瞻性验证。我们计划使用这种新的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的入选/排除标准。 通过对临床记录的分析，发现患者可分为重症和减重症 根据获得奖学金的情况分组。虽然这有助于回顾性分析，但确定 对象分类在通常是婴儿的新诊断患者中可能是困难的。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 糖胺聚糖（GAG-NRE）的终末物质，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 紊乱我们预计，总体GAG-NRE种类将在MSD患者中升高， 升高的幅度将与临床严重程度成比例。总的来说，MSD疾病量表和 当我们准备向有希望的方向迈进时，这里开发的生物标志物对临床试验设计至关重要。 临床前项目转化为首次人体试验。

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.