Development and application of spastin recovery therapeutic approaches in SPG4-HSP pre-clinical models

Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterised by progressive spasticity of the lower limbs The most common type of Hereditary spastic paraplegia (HSP) is due to mutations in the SPG4 gene, encoding the spastin protein. Several studies show that it is crucial to have the right amount of spastin in cells. Curative therapies and approaches to manage HSP progression are completely lacking. However, recent findings indicate that restore the proper dosage of spastin might be beneficial for spastin-deficient HSP patients. Thanks to Telethon support, we have identified and characterised a new druggable pathway regulating spastin levels. We demonstrated that it is possible to restore the correct spastin dosage and rescue HSP defects by pharmacologically preventing spastin degradation.

Therefore, to further extend and generalise these results, we now plan to confirm the efficacy of spastin elevating drugs in a cohort of neurons derived from cells of patients with different SPG4 mutations and in vivo in fly models of SPG4-HSP. In addition, to give these approaches a better chance of development, we will further detail the factors that regulate spastin to identify other more specific spastin elevating drugs and test their effects in preclinical models. Achieving these goals will provide the proof of concept that spastin elevating drugs are potentially a viable therapeutic strategy for SPG4-HSP.