Patient-Centric Clinical Outcome Measures for Multiple Sulfatase Deficiency (MSD) - PROJECT SUMMARY Multiple sulfatase deficiency (MSD) is an ultra-rare, fatal neurodegenerative disorder with emerging therapeutic options, including an AAV-based approach (Foundation for the NIH Bespoke Gene Therapy Program; PIs Adang and Ahrens-Nicklas). MSD is the result of dysfunctional sulfatase activation by the SUMF1- encoded formylglycine-generating enzyme (FGE). The resulting phenotype arises from the combined loss of all sulfatases. Our preliminary data suggest distinct phenotypes of MSD based on neurologic severity (severe and attenuated) that correlate with genotype and a novel biomarker of disease, glucosaminoglycan non-reducing ends (GAG-NREs). Because of its biologic similarity, we hypothesize that outcome measures employed in MLD and MPS clinical trials will be capable of capturing the impact of disease in this unique population. There is also a critical gap in our understanding surrounding the family's perspective of this ultrarare disease. The identification of patient-centric measures will be an essential step towards meeting the urgent needs of this rare disease community for future clinical trials. With our ongoing natural history study, we have the unique opportunity to address the critical need to (1) define patient-centric tools for measuring the burden of disease and defining clinical benefit and (2) validate the use of disease-specific scales in MSD for potential use as clinical endpoints in clinical trials. In Aim 1, the longitudinal performance of a panel of patient-centric assessment tools in 30 subjects will be captured. This includes the parent-reported measures including quality of life surveys and validated parent- reported assessments of functional abilities. This will be compared to standard provider administered outcome measures. As part of this aim, we will also create a rigorous study platform to support future research and regulatory needs. The expected outcome is a panel of objective measures that reflect patient and family perspectives on severity and importance that can be used as clinical trial endpoints in the upcoming MSD gene therapy trial. In Aim 2, existing tools developed for the single-sulfatase disorders will be applied to the MSD population. Within our prospective natural history cohort, we will compare the performance of these clinician reported outcome measures with more labor-intensive provider outcome measures and disease severity stratification by biomarkers and genotype. The expected outcome is the validation of additional outcome measures for clinical trial stratification. This work is significant because it will generate the tools necessary to define appropriate outcome measures to capture disease progression. These panel of measures defined in this project will be the foundation of imminent clinical trials. This work will form the basis of inclusion/exclusion criteria and selection of trial endpoints. Collectively, these efforts will form the components needed to design, conduct, and interpret clinical trials targeting MSD, a fatal and progressive disorder of childhood.
