Disease Severity Stratification in Multiple Sulfatase Deficiency

项目总结 多发性硫酸酯酶缺乏症(MSD)是一种极其罕见的多系统进行性神经退行性变 无序。死亡年龄中位数为13岁，目前还没有得到批准的疾病修正疗法。MSD 产生于编码甲甘氨酸生成酶(FGE)的SUMF1的致病变异体。 由于FGE必须激活所有的硫酸酯酶，所以MSD患者会患上 硫酸酶活性降低的组合效应。其中一些硫酸盐酶与油井- 描述的单基因疾病包括粘多糖症(MPS)和异色性的5种亚型 白质营养不良(MLD)。总体而言，MSD的症状和体征是进行性的，尽管具体的 功能可以是可变的。尽管在临床前模型中积极开发治疗方案， 缺乏反映MSD进展和严重程度的可靠、定量的指标。我们假设一个 疾病特异量表和新的糖胺聚糖生物标记物将捕捉症状负担和 疾病严重程度，以MSD为单位。 有几个活跃的临床前研究计划专注于开发新的MSD 治疗。基于AAV9的基因治疗改善了疾病的生化标志物，延长了小鼠的生存时间 MSD的小鼠模型。为了为未来的临床试验做准备，我们招募了30多名患者参加我们的 MSD自然历史研究和生物库。我们对这个数据集的初步分析揭示了关键的表型 某些特征，如运动和进食技能的丧失，似乎与疾病的进展和 基因分型。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结果 捕捉MSD有意义的临床症状进展的测量。我们将在我们的 回顾MSD队列，并对其进行前瞻性验证。我们计划使用这种新型的MSD量表来测量 在即将到来的临床试验中，纵向改变，对患者进行分层，并确定纳入/排除标准。 通过对临床病历的分析，我们发现，患者可分为重症患者和轻度患者 基于行走能力的分组。虽然这对回顾分析很有帮助，但确定 对于新诊断的患者来说，科目分类可能很困难，因为他们通常是婴儿。没有 建立了可以区分MSD亚组的生物标志物。在目标2中，我们将调查非减缩 糖胺多聚糖的最终种类(GAG-NRES)，积累在MSD中的独特低聚糖， 与疾病的严重程度相关。GAG-NRES在许多相关的MPS中是经过充分验证的生物标志物 精神错乱。我们预计MSD患者的总体GAG-NRE种类将会增加，并且 升高的程度将与临床严重程度成正比。总体而言，MSD疾病分级和 这里开发的生物标记物将是临床试验设计的关键，因为我们准备进行有希望的进展 临床前计划进入首个人体试验。

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.