DOI: 10.25934/pr00010717
title: The impact of genetic variation and phenotype on lysosomal diseases, and the identification of biomarkers for disease progression and response to treatment

description: Lysosomal storage diseases (LSD) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function (lysosomes are found in the body’s cells and they help break down, or digest, certain materials inside the cell such as proteins). LSD are caused by lysosomes not working correctly, usually as a consequence of deficiency of a single enzyme (a protein that speeds up chemical reactions inside the cells).

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare lysosomal disorder caused by mutations (changes) in the IDS gene, leading to a deficiency of an enzyme, iduronate-2-sulfatase (ID2S). The ID2S enzyme is responsible for breaking down certain compounds in the cells, and without it these compounds accumulate in the body tissues of MPS II patients. This results in a progressive disease affecting all tissues which can manifest in differing symptoms. The diseases can range from severe forms (with neurodegeneration – loss of nerve cells) to milder forms. 

Comprehensive analyses incorporating longitudinal clinical trial data, where measurements are repeated over a period of time, for MPS II are limited. Additionally, the identification of biomarkers (for example, specific genes, or molecules found in the blood) predictive of disease progression and therapeutic response remains an urgent unmet need. 

This research request seeks access to completed clinical trial datasets to systematically investigate genotypic heterogeneity (the presence of different genes in different people), the relationships between observable traits or conditions (a person’s phenotype) that can arise from genetic variations (a person’s genotype), and biomarker discovery in MPS II. Specifically, we aim to: (1) stratify patients based on genetic mutations, to assess their impact on disease severity and treatment response; (2) analyze clinical outcomes (e.g., cognitive function, mobility, pulmonary and cardiac function) in relation to genotype; and (3) evaluate biomarkers, to determine their predictive value in monitoring disease progression and response to enzyme replacement therapy (ERT, therapies that seek to replace a defective enzyme) or other investigational treatments. 

Access to these data would allow for a robust statistical analysis of how genetic variation influences disease trajectory and treatment efficacy. This study has the potential to refine patient stratification for clinical trials, enhance prognostic modelling, and identify surrogate biomarkers that could improve the design of future interventional studies. Findings from this analysis could inform precision medicine approaches in MPS II, optimizing therapeutic strategies based on genetic and biomarker profiles. We anticipate that the results will contribute valuable insights for the MPS II research community, regulatory decision-making, and the advancement of biomarker-driven therapeutic development. 

After evaluation of the requested data, we aim to expand this research project to additional Lysosomal Storage Diseases (LSD), including MPS III (San Filippo Syndrome), Niemann-Pick disease type C and Gaucher diseases. We will apply the same approach and will explore possible cross-diseases biomarkers discoveries, to the benefit of additional patients with other types of LSD.