Disease‐in‐a‐dish: drug discovery using patient‐derived stem cells in Hereditary Spastic Paraplegia

Abstract

Objective: Identify a drug treatment for Hereditary Spastic Paraplegia (HSP) using patient‐derived stem cell models\n\nBackground: HSP is a neurological disorder characterised by axonal degeneration of the corticospinal tract leading to lower limb spasticity. Mutations in the gene SPAST are the major cause of HSP. SPAST encodes Spastin, a protein involved in regulating microtubule dynamics.\n\nMethods: To understand the underlying disease mechanism and identify potential drug treatments, we used two sources of patient‐derived stem cell models: a) adult stem cells: olfactory neurosphere derived (ONS) cells, a population of neural progenitor cells (10 patient v/s 10 healthy control cell lines) and b) induced pluripotent stem (iPS) cell derived cortical neurons (6 patient v/s 5 healthy control cell lines).\n\nResults: Patient ONS cells have reduced Spastin, reduced stabilised microtubules, altered cellular distribution of organelles mitochondria and peroxisomes and impaired peroxisome transport1. When stabilised microtubule levels were restored in the patient cells using tubulin‐binding drugs, the peroxisome transport was also restored to control levels2. Patient ONS cells were under oxidative stress and more sensitive to oxidative stress induced by hydrogen peroxide. These were restored to control levels by tubulin‐binding drugs3. To test if our findings in the patient ONS cells are relevant in patient cortical neurons, we evaluated patient‐derived iPS cortical neurons. Patient neurons showed amplified disease specific deficits previously observed in patient ONS cells. Tubulin binding drugs, particularly Noscapine, rescued disease‐specific defects in patient neurons.\n\nConclusions: Based on our findings in patient‐derived stem cell models, we suggest a mechanism whereby SPAST mutations lead to reduced levels of stable microtubules which compromises axonal transport and leads to increased oxidative stress. These disease‐specific defects can be restored by treatment with tubulin‐binding drugs. We are now proceeding towards a clinical trial for Noscapine.