Disease Severity Stratification in Multiple Sulfatase Deficiency

点击翻译按钮获取中文摘要

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.