Abstract Details

Title A New Diagnostic Biomarker in the Study of Amyotrophic Lateral Sclerosis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P10 - Poster Session 10 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-002

Objective To introduce a new mechanism in ALS pathogenesis with relevance as a diagnostic assay .

Background

TDP-43 is mislocalized to the cytoplasm in ALS as a likely mechanism of disease pathogenesis. Using methods developed for study of virus pathogenesis, the mechanism of catalyzed protein assembly was identified as a relevant target in the pathophysiology of ALS. We have identified small molecules with an ability to modulate protein aggregation, analogous to their action in mechanisms of host-catalyzed viral capsid formation. We have termed these small molecules protein assembly modulators.

Design/Methods

Energy-dependent drug resin affinity chromatography (eDRAC) revealed signature alterations in composition of a peripheral blood mononuclear cell (PBMC) multi-protein complex in ALS patients compared to healthy individuals.

Blinded ALS patients and healthy individual blood samples were obtained under an IRB-approved protocol. Extracts prepared from PBMCs were applied to drug resin and the bound material analyzed.

Results Signature changes in the PBMC drug target in ALS patients compared to healthy individuals include diminished p62/SQSTM1 and appearance of a 17 kDa post-translationally modified form of RanGTPase. The ALS patient vs healthy control correlations involving p62 and Ran 17 kDa fragment were accentuated over time with progression of ALS. With disease progression the amount of PBMC p62 in the target multi-protein complex diminishes. and the amount of RanGTPase 17 kDa fragment, (missing in PBMCs from healthy individuals), increases.

Conclusions The eDRAC signatures observed appear to have a sensitivity for ALS approaching 100%, can be detected even before serious disability, and are correlated with disease progression. Specificity calculations are underway and will be presented. Our data suggest that this novel assay of catalyzed protein assembly may provide a tool for early detection of ALS using as an affinity ligand a small molecule efficacious in ALS small animal models.

Authors/Disclosures
Jeffrey Rosenfeld, MD, PhD, FAAN (Loma Linda University School Medicine - NEUROLOGY) PRESENTER	Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ML Biosolutions. Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for MT Pharma America. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CSL Behring. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Rosenfeld has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for NeuroSense. Dr. Rosenfeld has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Catalyst. Dr. Rosenfeld has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Annexion. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurizon. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Serano/EMD. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Anelixis. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AcuraStem. Dr. Rosenfeld has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NeuroSense. Dr. Rosenfeld has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for MT Pharma America. Dr. Rosenfeld has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Argenx. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Strongbridge Pharma. Dr. Rosenfeld has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amylyx. The institution of Dr. Rosenfeld has received research support from MT Pharma. The institution of Dr. Rosenfeld has received research support from Alexion. The institution of Dr. Rosenfeld has received research support from Healey ALS Trial Center Mass General.
Vishwanath R. Lingappa, MD, PhD	Dr. Lingappa has received personal compensation for serving as an employee of Prosetta Biosciences . Dr. Lingappa has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Akonni Biosystems. Dr. Lingappa has stock in Prosetta Biosciences. Dr. Lingappa has received publishing royalties from a publication relating to health care.

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