Research project on target
Principal researcher of the HSP stem cell project, and Director of the National Centre for Adult Stem Cell Research, Professor Alan Mackay-Sim provided the following progress report on 13 May, 2011.
Identifying therapeutic drug candidates for treating HSP
The project has advanced according to schedule, with the first four aims achieved and the fifth currently progressing:
1. increase understanding of the consequences of changes caused by mutations in the SPG4 gene, the most common HSP related gene, responsible for 40% of all HSP occurrence.
Everyone has two copies of every gene. These people have one “good copy” and one “bad copy”. We have shown for the first time that patients have a 50% loss of the spastin protein (made from the SPG4 gene). This means that they cannot compensate for the loss of one gene copy by just making more protein from the good copy. This is a new understanding of how the gene mutation works to cause disease. It immediately rules out several hypotheses that people had about the disease. We have shown for the first time that although patients cannot compensate by making more spastin, they compensate by making more of other proteins that work in parallel, with the result that overall, many cell functions are “normal”. This must be true because SPG4 mutations only affect specific nerve cells, in adult life, so the cellular compensations are effective for most cells for all of life and only fail in specific nerve cells in adulthood. Our research now points us to how cells compensate and where they do not.
2. lead to an understanding of the major cellular dysfunctions: detect the dysfunctions/abnormal behavior in cellular pathways; what cell functions are changed/how do cells work in a disease situation.
We have identified for the first time specific cellular pathways that are not fully compensated in patient cells. These new results support existing hypotheses, based on other’s experiments exploring spastin function in non-patient cells. The new results also point to new hypotheses of what is going wrong.
3. define and describe specific cell functions as candidate targets for therapeutic drugs.
We have identified specific changes in microtubule functions inside cells. Microtubules form part of a cell’s “skeleton” at the same time as forming a “roadway” for transporting the specialised “organelles of cell function” around the cell. We have shown for the first time that patient cells have less of one of the proteins that constitute the microtubules. We have identified for the first time two types of organelles whose transport is affected.
4. devise assays for subsequent screening of therapeutic drugs against the target cell functions.
We now have three assays that may be suitable for screening drug libraries: assays for the microtubule proteins and assays for the organelles. Our institute recently purchased the instrument on which the assays were devised when it was on loan from the company. The instrument costs $500K.
5. validate the assays.
We are just starting the validation phase. We have a strategy based on an understanding of the known functions of the spastin protein and on our own experiments, with drugs known to interfere with microtubule function.