National Institute of Neurological Disorders and Stroke 1R21NS149629-01

Testing a new therapy for SPG4 Hereditary Spastic Paraplegia

This award funds research to develop and test intrabody therapeutics targeting mutant spastin protein in SPG4 Hereditary Spastic Paraplegia, aiming to halt and reverse neurodegeneration using patient-derived stem cell models.

Description

Hereditary Spastic Paraplegia 4 (SPG4-HSP) is an underdiagnosed neurodegenerative disorder characterized by progressive weakness and spasticity in both legs that escalate into wheelchair dependence. Symptoms result mainly from dying-back degeneration of corticospinal tracts. The disease is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Recent studies indicate that disease pathology is primarily driven by the M1 isoform of spastin, which, when mutated, becomes toxic. A therapeutic strategy involves reducing mutant M1 levels and restoring axonal integrity to halt and reverse disease progression. A multi-PI team at Drexel University has developed monoclonal antibodies specific for M1, engineered into intrabody vectors for intracellular expression in affected neurons, including a lysosome-targeting sequence for degradation. Using patient-derived hiPSC lines differentiated into motor cortical organoids (MCOs), the team will test whether degrading mutant M1 restores cellular homeostasis and reverses neurodegeneration.

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