Hereditary spastic paraplegia (HSP) is a genetically heterogeneous motor neuron disorder that causes significant gait disturbance and disability. There are at least 40 different genes that are implicated in HSP, but many of these are rare, with only a few affected families worldwide. It is estimated that half of HSP cases are due to mutations in the spastin gene (Spast), which encodes a protein that regulates the cytoskeleton.
There is currently no cure for HSP patients. Pharmacological treatment of HSP patients is limited to the use of muscle relaxants to reduce symptoms of spasticity. Dr Andy Grierson leads a team of researchers based in SITraN at the University of Sheffield. The current focus of HSP research in SITraN is to use disease models to identify new therapeutic approaches.
His team previously developed a spastin mouse model that closely mimics human disease. Mutant spastin mice develop a progressive spastic gait very similar to human HSP patients. Pathologically, the mice show swelling pathology in the spinal cord which closely resembles the swelling pathology in axons located in the spinal cord of HSP patients.
The current project is focused on developing new therapeutic approaches for treatment of HSP caused by spastin mutation. Several strands of evidence all suggest that disruption to transport and trafficking in the long axons of motor neurons is responsible for the disease symptoms in HSP. Recently several different groups working with cells obtained from mouse models and patient derived cells have provided evidence that microtubule-binding drugs might be beneficial to patients.
BMS-241027 is one such drug that has already been used successfully in mouse models of Alzheimer’s disease, dementia, Parkinson’s disease, and schizophrenia. Importantly this drug was previously shown to be beneficial in a human stem cell model of spastin HSP, and the drug was shown to be safe when administered in a Phase I clinical trial in humans (with Alzheimer’s disease). Therefore this drug is an excellent candidate for clinical development in HSP. The goal of the current research project is to test the effect of BMS-241027 treatment in the HSP mouse model.
Dr Grierson said “Modulation of the cytoskeleton is an attractive drug target for HSP. As a first step we hope to determine whether BMS-241027 can improve the spastic gait in a mouse model of HSP. We hope that our investigation paves the way for further research in this area.”
The University of Sheffield acknowledges the generous provision of BMS-241027 by Bristol-Myers Squibb, and funding from the HSP Support Group (UK).