Research Project 2

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

Investigators

Abstract

PROJECT 2: BIOMARKER DISCOVERY – PROJECT ABSTRACT The neuronal ceroid lipofuscinoses (NCLs) are rare neurogenetic diseases caused by mutations in one of 13 CLN genes, leading to lysosomal dysfunction, neuroinflammation, and neurodegeneration. These conditions, with an incidence of 2-4 per 100,000 births, primarily affect children and result in progressive loss of vision, motor dysfunction, dementia, , and early death. Given the variability in symptoms and progression, there is a significant need for reliable, quantifiable biomarkers to differentiate, and monitor NCLs. Biomarkers, including molecular, imaging, or physiological measurements, can help to assess disease progression and treatment response and are crucial in clinical trials for evaluating treatment efficacy and can support regulatory approval. For NCLs, minimally invasive, sensitive, reliable biomarkers that correlate with disease progression are critically needed for monitoring disease and to act as surrogate endpoints for assessing therapeutic effects. Building on previous work, our long-term goal is to develop a panel of disease-specific biomarkers and a longitudinal biosignature scoring system that reflects NCL pathophysiology to enhance clinical trial readiness by providing actionable endpoints for monitoring disease progression and therapeutic response for CLN1, -2, -3, and -6 disease. Through our proposed aims, we will use high-content -omics approaches to overcome challenges in rare disease biomarker discovery. Specifically, we will identify novel metabolomic, lipidomic, and proteomic biomarkers using comprehensive -omics analyses of patient biofluid samples collected longitudinally with the goal of generating datasets to identify and confirm biomarkers at various stages of disease progression. We will analytically and clinically verify the most promising biomarkers to ensure their effectiveness and sensitivity. Our preliminary studies have uncovered several biomarkers in large animal models of CLN1, -2, -3, and -6, providing lead candidates for initial verification. To expand these efforts, we will perform a comprehensive multi-omics biomarker discovery with existing patient biofluid samples and new samples collected by the BDCRC during this project. Next, we will approach our -omics and clinical data collected in the BDCRC to develop a biomarker scoring framework. Initially, we will focus on the extensive data sets identified in our -omics assays and utilize a data science approach to build a disease-specific scoring system corresponding to early, mid, and late stage for each NCL. We will combine our -omics analyses with clinical kinematic and physiologic measurements, and laboratory data to create a unified biomarker score adaptable to different NCL forms. Leveraging our prior experience with DIABLO/sPLS-DA modeling in CLN3 disease, we will collaborate with the BDCRC Administrative Core to integrate and analyze data, resulting in a comprehensive scoring system. Collectively, this study will establish sensitive and robust NCL biomarkers, enabling timely outcome measures for clinical trials, allowing for accelerated therapeutic development and improving NCL management by providing reliable tools for monitoring disease progression and treatment response.