On Saturday July 22nd Cinzia Rinaldo gave a presentation to the group about the work that her research group has been doing in Italy. The HSP Support Group part-funded this research, and the presentation was to inform members about their new findings.
She outlined the different people involved in her laboratory and their partners/collaborators. There have been two different aspects of the project, which focuses on the SPG4 type of HSP, where the genetic mutation is in the Spastin gene. Where spastin is affected by HSP its effectiveness is reduced, and therefore it is unable to do its job within cells as well.
- Firstly, they are seeking to increase the levels of Spastin by reducing its degradation. They note that this is a possible therapeutic approach for HSP. They have been testing the drug MLN4924.
- Secondly they are trying to identify biomarkers for SPG4 to make it easier to detect when drugs are working.
Spastins job within the cells is to cut microtubules. Most people affected by SPG4 have one copy of spastic which functions properly, and one copy which does not. Therefore, the microtubule cutting is not done as effectively in those with SPG4. The approach for the study is to target recovering the level of spastin in the cells to allow it function better.
Their study seeks to answer three questions;
- How are the levels of spastin regulated within the cell?
- How can the levels be increased?
- How can the recovery of spastin levels be detected?
Regulation
They identified a pathway which regulates spastin, and this pathway can be modified by drugs. There is an inhibitor which can be used to block the degradation of spastin within the cell. Their research also explored all of the different factors which can elevate the levels of spastin, allowing other pathways to be identified in the future.
The drug MLN4924 is currently being trialled as a cancer treatement, and has been demonstrated to block the degradation of spastin in cells. They are hoping to re-purpose the drug for use in HSP.
Increasing levels
They have been testing MLN4924 using animal models of HSP. With the HSP mouse, this doesn't usually have any copies of spastin. When the mouse has one copy of spastin the HSP effects are small and occur late in its life. A mouse with no spastin is not a good choice to test methods to recover spastin.
However, the fruit fly model of HSP has spastin, and it is easy to detect the changes in the fly as a result of changes in spastin. Cinzia showed photos of fruit flies, an un affected one, one with the spastin mutation, and one with both spastin mutation and the treatment. They demonstrated that the levels of spastin are recovered using the treatment.
Detecting change
The team have developed a non-invasive cell imaging method to be able to detect the effects of spastin (or lack of) in blood cells. The team can use the imaging to identify both cells which are affected by lack of spastin, and the effects of the drug being trialled.
This work has been published: https://onlinelibrary.wiley.com/doi/10.1111/ene.15756
Next Steps
She concluded by describing the next steps for their team.
The want to extend their cohort of people affected by HSP to be able to consolidate their biomarker results and potentially develop more.
They are going to investigate the spastin elevating drugs and their impacts on cells
The want to develop prognostic and predictive methods for tracking spastin in non-neural cells.
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