Plasma Biomarkers for ALS & Related Disorders

University Of Miami School Of Medicine, Coral Gables FL

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY (Project 3: ALSRD Biomarkers) Therapy development for amyotrophic lateral sclerosis (ALS) and related disorders (ALSRD), including progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS), is hampered by a paucity of biomarkers that are fit for purpose. We have identified three different contexts-of-use for which development of plasma biomarkers would have immediate relevance to drug development programs. These include (1) prognostic biomarkers that when measured at baseline, have value in predicting the future course of disease; (2) monitoring biomarkers that are measured longitudinally and whose natural history in the untreated state is well characterized and might change over time or be elevated/depressed relative to controls but stable over time; and (3) predictive biomarkers that can identify individual patients most likely to respond to a therapeutic targeting a particular mechanism of action. The latter are critically lacking for non-genetic forms of disease that comprise ~85% of ALSRD. The proteome is an understudied yet potentially important source of information about differentially expressed proteins in ALSRD. However, to date blood proteomic studies of ALSRD have many limitations, including evaluation of 100s-1000s of analytes in only 10s of individuals, and have had limited sensitivity to low concentrations of blood proteins. Critically these proteomic studies have been cross- sectional and have sought to differentiate ALS from controls, but have not addressed related disorders like PMA and PLS or considered potential context-of-use in the analytic strategy. In this project, we will perform the first application of NUcleic acid Linked Immuno-Sandwich Assay (NULISA) in ALSRD that has many technical innovations and increased sensitivity over prior methods. We additionally innovate using multivariate and unsupervised data-driven strategies to identify novel markers that improve upon prognostication methods, are longitudinally sensitive or stably elevated/depressed, and might stratify patients with molecular subtypes of ALSRD. We propose to specifically focus our discovery efforts using a central nervous system (CNS) targeted panel of ~120 analytes that spans several molecular pathways previously implicated in ALSRD and leverage a longitudinal cohort of 250 ALSRD spanning ALS, PMA, and PLS with deep clinical characterizations. Specifically, we aim to discovery novel (1) prognostic plasma biomarkers that improve upon established European Network to Cure ALS clinical prediction model and blood neurofilament light based predictions of functional decline and survival; (2) monitoring plasma biomarkers that might have future use as response markers; and (3) predictive plasma biomarkers that identify ALSRD biological subtypes and might be used for targeted interventions in future clinical trials. Together, through careful consideration of these contexts-of-use alongside novel proteomic and bioinformatics strategies, this inter-disciplinary team project leverages established CReATe resources to empower discovery and validation of biomarker candidates that are fit-for- purpose in facilitating therapy development for ALSRD.