Mulltifunctional Radical Quenchers for the Treatment of Mitochondrial Disorders Evaluation in Cellular Disease Models Evaluation in Cellular Disease Models As noted in the attached summary of our studies on multifunctional radical quenchers (MRQs), the underlying biochemical issues in the cells from patients with many mitochondrial diseases are likely to be similar, and it is logical to believe that our MRQs may be able to blunt disease progression in a number of mitochondrial disorders. Accordingly, we have carried out some work to evaluate this possibility. This has been done using representative MRQs and a limited number of cell lines. As shown in the attached summary, our MRQs protected a number of cultured cell lines from the effects of induced oxidative stress. These included an Alzheimers disease cell line (Coriell AG06849 lymphocytes, containing a mutation in the PS1 gene), a Parkinsons disease cell line (Coriell GM15010 lymphocytes, gene triplication including synuclein SNCA, classified as PARK4), and LHON lymphocytes (Coriell GM10744, mutation in the NADH dehydrogenase subunit 4 gene MTND4, in complex I). All of these cell lines could be protected quite effectively by a number of MRQ derivatives, some of which were completely cytoprotective at 500 nM concentration. This was also found to be true for Leighs syndrome lymphocytes (Coriell GM1370). These cells were tested in comparison with FRDA lymphocytes (Coriell GM15850), and found to respond quite well to the MRQs. Also shown in the summary is the effect of selected MRQs on SH-SY5Y cells, a differentiated neuroblastoma cell line used extensively in Alzheimers disease research. Again, the MRQs conferred significant cytoprotection, this time against ROS produced by a challenge with A1-40. Interestingly, SH-SY5Y cells are known to have significantly reduced ATP levels. Treatment with selected MRQs strongly increased the ATP level in this cell line. In parallel with the progression of our lead MRQ for the treatment of Friedreichs ataxia, it would be of great advantage to be able to broaden our study of the MRQs in cellular models of other mitochondrial diseases. To date we have not had the resources to verify that the cytoprotective effects described above for the several types of cell lines studied are due to the same biochemical effects that we have shown to benefit Friedreichs ataxia cells (i.e. quenching of lipid peroxidation, suppression of lipid peroxidation, maintenance of mitochondrial membrane potential, augmentation of ATP levels). Additionally, it should be noted in the attached summary that the cytoprotective results obtained in different cell lines for single MRQs were somewhat variable. That is, at least at the level of cell culture, the MRQ predicted to confer maximal benefit to one type of disease cell did not necessarily work optimally in other lines. At present, the choice of an MRQ optimal for therapeutic intervention is being made primarily based on its use for the treatment of FRDA. The variability in the data in the summary suggests strongly that the selection of an agent for the treatment of a broader range of mitochondrial disorders might be carried out more appropriately by surveying a significantly broader variety of cell lines from patients with those mitochondrial disorders. The methods required to assure the generality of the biochemical effects of our MRQs in different types of cell lines, and to select a small number of MRQs that function effectively in numerous cell types, have all been developed and are currently available in the Center for BioEnergetics. Deliverables for this proposed project include the acquisition of biochemical data to assure that the compounds work in a similar fashion in different cell lines with impaired mitochondrial function, and the identification of a set of preferred MRQs that can be used to identify one or more drug candidates for the treatment of a variety of mitochondrial disorders.
|Effective start/end date||9/17/12 → 10/31/13|
- United Mitochondrial Disease Foundation: $105,293.00
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