Federal Project Grant Award Summary

Drexel University received a $228,688 Project Grant award from the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853), with an award date of June 15, 2026, and completion date of March 31, 2028. The grant supports research to develop and validate a novel therapeutic approach for Hereditary Spastic Paraplegia 4 (SPG4-HSP), a progressive neurodegenerative disorder caused by mutations in the SPAST gene. The research team has engineered three recombinant monoclonal antibodies (intrabodies) designed to selectively target and deplete the mutant M1 isoform of spastin protein, which accumulates and becomes toxic in affected neurons, while minimizing impact on the wildtype protein.

The primary deliverables include preclinical research utilizing human induced pluripotent stem cell (iPSC)-based platforms to test the intrabody therapeutic approach, including development of isogenic iPSC lines with distinct SPAST mutations and patient-derived iPSC lines differentiated into motor cortical organoids (MCOs). Research outputs will address key questions regarding the efficacy and sustainability of mutant M1 depletion, off-target toxicity risks, and mitigation strategies for potential effects on wildtype M1. This investigation aims to validate the intrabody approach as a potential breakthrough therapy for SPG4-HSP and provide foundational data supporting translational advancement of this therapeutic strategy.