Yeah, so as people know, age is the major risk factor for Alzheimer’s disease, as well as other forms of dementia. And so we decided a number of years ago that in order to prevent the development and progression of the disease, that compounds or drugs were needed that possibly could prevent the changes that are known to occur in the aging brain. And we believe contribute to disease development and progression...
Yeah, so as people know, age is the major risk factor for Alzheimer’s disease, as well as other forms of dementia. And so we decided a number of years ago that in order to prevent the development and progression of the disease, that compounds or drugs were needed that possibly could prevent the changes that are known to occur in the aging brain. And we believe contribute to disease development and progression. And so to identify such compounds, we developed a set of cell-based phenotypic screening assays that we believe mimic the various changes that occur in the aging brain and lead to disease development. These assays include protection against a cell death pathway called ferroptosis, which we have found mimics many of the changes that occur in the aging brain, including losses in the major intracellular antioxidant, glutathione, increases in lipid peroxides, as well as the activity of lipoxygenases, which generate lipid peroxides, increases in iron, mitochondrial dysfunction, and calcium dysregulation. And as I said, all of these changes are seen in the aging brain, and they are known already to be exacerbated in the context of Alzheimer’s disease. So we use this as our primary screen. We also included assays for protection against energy loss, for protection specifically for Alzheimer’s disease against Aβ toxicity, neurotrophic. We wanted compounds that had neurotrophic activity, and we also wanted compounds that had anti-inflammatory activity. So the goal was to identify lead drug candidates that had all of these activities. And so we began by screening a library of flavonoids. These are natural products. They’re abundant in plants. There’s over 4,000 of them. And we chose these because they were already known to often have multiple targets. And since we wanted to be able to tackle a broad array of changes, we thought compounds that potentially had multiple targets might be most effective. Using this approach, we identified a flavonoid called fisetin that was very effective in all of the assays. And so we decided to use this as our lead to develop a somewhat better compound because fisetin itself doesn’t get into the brain very well. And while it’s quite effective, we thought we could improve its activity. And so we made a library of fisetin derivatives and screened all of those in our screening, our assays. And we ended up focusing on two of the products, well, several of the products, some of which we found using pharmacokinetic studies didn’t get into the brains of mice and ended up focusing on two. We took those into a mouse model of, a transgenic mouse model of Alzheimer’s disease. And one of them, CMS-121, was very effective at actually reversing symptoms in the mice. So in that study, we took mice that were nine months of age where they already have cognitive problems, and we were able to show that we could reverse those cognitive problems. And that correlated with increases in synaptic proteins, reductions in markers of inflammation, as well as reduction in markers of this activation of this ferroptosis pathway. We’ve done further studies looking at the relevance of this ferroptosis pathway to Alzheimer’s disease using publicly available transcriptomic databases. And we have shown that indeed transcriptional changes that are associated with, excuse me, activation of this pathway are increased in the brains of patients with Alzheimer’s disease in the areas of the brain that are specifically affected in Alzheimer’s disease, such as the hippocampus, then the temporal cortex and the entorhinal cortex. Whereas there are actually, these markers are not increased in areas of the brain, such as the cerebellum that are not nearly as much impacted in the context of Alzheimer’s disease.
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