Project Grant R21NS149721

This $195,000 Project Grant, awarded by the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853), funds research conducted by Thomas Jefferson University to investigate RNA G-quadruplex (GQ) structures as therapeutic targets for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The award, obligated May 19, 2026, with completion scheduled for April 30, 2028, supports fundamental and translational research addressing aberrant RNA processing caused by TDP-43 (TAR DNA-binding protein 43) dysfunction in these neurodegenerative diseases.

The research deliverables encompass two primary aims: (1) computational prediction, transcriptome-wide mapping, and biophysical validation of GQ structures at TDP-43-regulated cryptic exons in patient-derived neurons using techniques including circular dichroism, fluorescence resonance energy transfer (FRET), and fluorescence anisotropy; and (2) development and optimization of small-molecule compounds that selectively bind and stabilize GQs through an integrated deep-learning discovery platform combining junction tree variational autoencoders with random forest classifiers. These research outputs are intended to identify disease-relevant GQ targets and lead compounds that may compensate for TDP-43 loss and restore normal splicing fidelity, thereby providing a novel therapeutic approach to ALS/FTD treatment.