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For those catching up: our core hypothesis centers on excitotoxic calcium overload, a process in which motor neurons are overwhelmed by too much calcium flowing in through their own receptors. Specifically, we're focused on calcium-permeable AMPA receptors, or CP-AMPARs. Under normal conditions, AMPA receptors let neurons communicate safely. But a subset of these receptors becomes unusually permeable to calcium, and when that happens, they let in far more calcium than a motor neuron can handle. This mechanism itself isn't new; it has been studied for decades. What's novel in our approach is the hypothesis, and now growing evidence, that this pathway is active across multiple subtypes of ALS, not just sporadic ALS or a single genetic form.
As we've discussed before, we view ALS as a threshold problem rather than a single disease with a single cause. Every neuron can tolerate a certain amount of stress, genetic, metabolic, or environmental, without dying. Disease onset and progression happen when the cumulative burden of these stressors crosses a critical threshold, tipping the neuron from a stable state into decline. The variance in progression, patient-to-patient, represents how well one can compensate before crossing this threshold. Because that threshold can be reached through many different combinations of contributing factors, we believe a therapy that meaningfully reduces even one major convergent driver, in our case pathological calcium influx through CP-AMPARs, has the potential to help patients regardless of which genetic or sporadic form of ALS they have.
That thinking is already bearing out in our own data. Published research has shown this pathway is active in C9orf72, the most common inherited genetic risk factor for ALS. We're now seeing the same pattern in our own iPSC models carrying two separate ALS-related TARDBP mutations (the gene governing TDP-43, a protein implicated in the vast majority of ALS cases regardless of cause).
Even more significantly, we used tool compounds to isolate and map the source of these calcium ions to identify their point of entry. We found that nearly 60% of the pathological calcium influx came through CP-AMPARs, the very receptor we've been targeting. We then used selective tool compounds to demonstrate that this influx can be effectively blocked, all while leaving healthy, calcium-safe AMPA receptors untouched.
This matters because it reinforces the core premise of our approach: developing precision medicines that selectively inhibit pathological receptor activity while preserving normal, healthy receptor function. It's a modern, targeted take on the decades-old calcium excitotoxicity hypothesis, one we believe was never properly pursued to its full potential.
Additional research is now underway to evaluate our novel compounds as candidates for our lead therapeutic program, CRTX-101.
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