Posted - June 2014 in Research Highlights
Potential for future clinical trials
Australian HSP research has identified 2 promising drug candidates with the potential to effectively treat HSP. Further trials are needed this year and next to validate the potential of these drugs as the basis for getting approval for human clinical trials.
This paper reports research proudly supported by this Foundation. Read the full paper.
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.
SOURCE: Biol Open. 2014 May 23. pii: BIO20147641. doi: 10.1242/bio.20147641. [Epub ahead of print] © 2014. Published by The Company of Biologists Ltd. PMID: 24857849 [PubMed – as supplied by publisher]
Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia.
1National Centre for Adult Stem Cell Research, Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
2Kolling Institute for Medical Research, University of Sydney, Sydney, NSW 2065, Australia.