Research Investigations of Cellular Stress in Development and Diseases

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications, trials & patents

Abstract

The Unit on Cellular Stress in Development and Diseases was established in October 2021, and completed recruitment of laboratory personnel in April 2022. We are developing laboratory reagents, experimental models, and collaborations to address the overall objective of understanding the role of the integrated stress response in human diseases such as CLN3. We continue to conduct extensive characterization of the phenotype of individuals with variants in CLN3, and establish a biorepository of corresponding biosamples (CSF, blood, urine) NCT03307304. To date, our study contains the largest cohort of individuals with CLN3-related disorders extensively characterized and prospectively followed with corresponding biosamples collected. This 1) enables the development and assessment of outcome measures applicable for therapeutic trials (CRADA with Amicus Therapeutics), 2) builds the infrastructures for engagement in a sponsored Phase 1/2 study of miglustat therapy trial (CRADA with Beyond Batten Disease Foundation), and in future investigator-initiated and sponsored interventional trials, and 3) provides the means to further CLN3 research through identification of disease reflective biomarkers. Using CSF samples from the natural history study, we identified neurofilament light chain as a potential marker for disease monitoring (Dang Do et al. 2020), and glycerophosphodiester species as potential marker(s) for disease diagnosis (Brudvig et al. 2022; Laqtom et al., manuscript accepted). Biomarker discovery efforts will continue through the use of commercial platforms (Olink proximal extension assay), and through extramural collaborations to perform proteomic (David Sleat, Rutgers, NCL-Stiftung Research Award), transcriptomic (Susan Cotman, Mass General), and metabolomic/lipidomic (Monther Abu-Remaileh, Stanford) analyses of samples from Clinical and Basic Science projects. We also continue to work with collaborators (Jon Brudvig and Jill Weimer, Sanford Health) on translating candidate biomarkers to screening applications.