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:10513906
- 负责人:
- 金额:$ 23.25万
- 依托单位:
- 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:
- 关键词:Adaptive BehaviorsAddressAdvocacyAgeAspartylglucosaminuriaAttenuatedBiochemical MarkersBiological AssayBiological MarkersBiological Specimen BanksCell TherapyCessation of lifeChildChildhoodChondrodysplasia PunctataChondroitinClassificationClinicalClinical TrialsClinical Trials DesignCollectionDataData SetDeficiency DiseasesDegenerative DisorderDevelopmentDiseaseDisease MarkerDisease ProgressionDisorder of neurometabolic regulationElementsEnrollmentEnzymesExclusion CriteriaExhibitsFDA approvedFatigueFloorFoundationsFundingFutureGAG GeneGenotypeGlycosaminoglycansHeparitin SulfateHumanIndividualInfantLaboratoriesLettersMeasurementMeasuresMediatingMedical RecordsMendelian disorderMetachromatic LeukodystrophyMotorMucopolysaccharidosesMucopolysaccharidosis IINatural HistoryNervous System PhysiologyNeurodegenerative DisordersNeurologicNewly DiagnosedOligosaccharidesOutcomeOutcome MeasurePathogenicityPatientsPerformancePhenotypePilot ProjectsPopulationPopulation ControlPre-Clinical ModelProspective StudiesProtocols documentationRecordsReportingResearchRetrospective cohortSamplingSeveritiesSeverity of illnessSigns and SymptomsStratificationSubgroupSulfatasesSymptomsTestingTherapeuticUrineValidationVariantWorkX-Linked Ichthyosisbasebiobankburden of illnesscase controlclinically relevantcohortcombinatorialdesigneffective therapyenzyme activityexperiencefeedingfirst-in-humanformylglycinefunctional outcomesgene therapyimprovedinnovationmouse modelnovelnovel markerpatient stratificationpre-clinicalpre-clinical researchprogramsprospectiveskillssmall moleculespecific biomarkerstheoriestherapeutic developmenttool
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rebecca Clare Ahrens-Nicklas其他文献
Rebecca Clare Ahrens-Nicklas的其他文献
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{{ truncateString('Rebecca Clare Ahrens-Nicklas', 18)}}的其他基金
Network modulation to improve gene therapy in CLN3 disease
网络调节改善 CLN3 疾病的基因治疗
- 批准号:
10579621 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
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:
10700164 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
Network modulation to improve gene therapy in CLN3 disease
网络调节改善 CLN3 疾病的基因治疗
- 批准号:
10626675 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
The 2021 Multiple Sulfatase Deficiency Scientific and Family Meeting
2021 年多种硫酸酯酶缺乏症科学和家庭会议
- 批准号:
10318766 - 财政年份:2021
- 资助金额:
$ 23.25万 - 项目类别:
Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis
幼年神经元蜡质脂褐质沉积症神经元网络功能障碍的机制
- 批准号:
9789984 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis
幼年神经元蜡质脂褐质沉积症神经元网络功能障碍的机制
- 批准号:
10004182 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis
幼年神经元蜡质脂褐质沉积症神经元网络功能障碍的机制
- 批准号:
10457437 - 财政年份:2018
- 资助金额:
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Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis
幼年神经元蜡质脂褐质沉积症神经元网络功能障碍的机制
- 批准号:
10248394 - 财政年份:2018
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$ 23.25万 - 项目类别:
Investigation of arrhythmias in anthropomorphized murine cardiac myocytes.
拟人化小鼠心肌细胞心律失常的研究。
- 批准号:
7544841 - 财政年份:2008
- 资助金额:
$ 23.25万 - 项目类别:
Investigation of arrhythmias in anthropomorphized murine cardiac myocytes.
拟人化小鼠心肌细胞心律失常的研究。
- 批准号:
7690884 - 财政年份:2008
- 资助金额:
$ 23.25万 - 项目类别:
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