Therapeutic strategies to treating hereditary spastic paraplegias

Anjon Audhya, PhD, Department of Biomolecular Chemistry , University of Wisconsin-Madison, United States of America 

Project Summary

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of gait disorders characterized by progressive weakness (paraplegia) and stiffness (spasticity) of the legs, which often result in paralysis. Treatment consists of physical therapy, but no intervention is currently available to slow progression of disease. The pathological hallmark of HSPs is length-dependent distal axonopathy of nerve fibers in the spinal cord. Involvement of other neurons can cause additional symptoms, which define a diverse set of complex HSPs. We have focused our efforts on understanding how mutations in SPG57 lead to complicated forms of HSP, developing physiologically-relevant human stem cell and rodent models using CRISPR technology. Leveraging these systems, we will determine whether altering endoplasmic reticulum (ER) stress signaling is sufficient to ameliorate disease phenotypes in vivo and in vitro. Additionally, we will test the efficacy of a gene therapy-based approach using our new rodent model of HSP. Specifically, we have developed methods to drive SPG57 expression in a cell type specific manner in vivo, which will enable us to determine whether neurons or other cell types in the brain play a more prominent role in maintaining motor function. Our studies will also reveal the utility of therapeutic intervention at different timepoints as neurodegenerative disease progresses.


On the picture from front going back (right to left): Anjon Audhya, Molly Lettman, Shalini Shatadal, Jennifer Peotter, Raakhee Shankar, Peter Luong, Elisa Frankel, Iryna Pustova, Kyle Quinney, William Kasberg, Aryel Clarke, Sam Block