- Collect CSF in participants with AT, ATLD, AOA1, AOA2, and several mitochondrial ataxias (ARSACS, SPG7, POLG), and development of an ELISA based method for quantification of PARylated CSF protein.
Recent work has sought to cluster ARCAs more broadly based on underlying pathobiological mechanisms (reviewed in Synofzik et al. Neuron 2019) into those with impaired DNA repair, mitochondrial disorders, and lipid metabolism. This is an attractive way to group these disorders from a therapeutic standpoint, in order to increase statistical power for these rare disorders. Unfortunately, no biomarkers for target engagement in these disorders is present. In order to plan for clinical trials with promising agents on the horizon, biomarkers for target engagement are essential. CSF levels of poly(ADP) ribose-modified proteins may serve as a biomarker for monitoring both DNA strand breaks and NAD+ depletion. This may therefore serve as a biomarker for disease activity in both DNA strand-break and mitochondrial disorders. Unlike metabolites with a short half-life, PARylated protein levels in CSF would be expected to reflect longer term trends in impaired neuronal function. I propose CSF collection in participants with AT, ATLD, AOA1, AOA2, and several mitochondrial ataxias (ARSACS, SPG7, POLG), and development of an ELISA based method for quantification of PARylated CSF protein.
|Cohorts used||AT, ATLD, AOA1, AOA2, ARSACS, SPG7, POLG|
|Funding available?||To be sought|
|Trial readiness category||2: setting the stage for trial readiness (general cohorts, outcome measures or treatment approach identification)|
University of Texas, Southwestern Medical Center, Dallas, Texas, USA