Unten eingestellt ist eine Forschungsarbeit, der australischen HSP-Forscher. Sie stellt dar, welche Forschungsarbeit in Australien durchgeführt wurde, um Medikamente zu finden, die bei einer Mutation im SPAST-Gen (=SPG4) helfen könnten. Die Arbeit der Australier an diesem Projekt ist im Forum „Ge(h)n mit HSP“ kontinuierlich dargestellt worden. Die entsprechenden Berichte sind im Beitrag „Neues zum Projekt unserer australischen Freunde“ zu finden.
Unten eingestellt ist das Abstract zur Veröffentlichung. Der Langtext kann hier im Original und hier in der Google-Übersetzung aufgerufen werden.
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Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia
Yongjun Fan, Gautam Wali, Ratneswary Sutharsan, Bernadette Bellette, Denis I. Crane, Carolyn M. Sue, and Alan Mackay-Sim,
ABSTRACT
Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated α-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated α-tubulin in patient-derived ONS cells. Drug doses that restored acetylated α-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 µM noscapine) that rescued acetylated α-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated α-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials.