Cortexa Weekly— July 5th 2025
Cortexa Progress
I'll start off by saying I’m sorry it’s been a month since the last update. We just completed our move from Florida back to Arizona, and I wanted to make sure all of our fundraising efforts were fully in place before reaching out again.
That said—this pause hasn’t meant a slowdown. Our library of potential CP-AMPAR targeting compounds has grown to over 300 analogues. We're now consistently running them through in silico modeling to assess binding affinity, blood-brain barrier penetration, CNS MPO scoring, and off-target risk. This triage lets us zero in on the most promising candidates before synthesis.
We’ve been refining scaffolds to improve pharmacokinetics while reducing potential liabilities like QT prolongation. The end goal? A dual-mechanism therapy that blocks excitotoxic calcium influx without derailing normal brain function—a first in ALS drug development.
Fueling the Mission: Powering Discovery with Purpose
This week, we're shifting gears. Instead of our usual research updates, I want to talk about something even more foundational—funding the science that could change everything.
We’ve officially kicked off fundraising on two fronts:
Nonprofit Donations via Mission Edge — Our fiscally sponsored project is called Precision ALS, Powered by the Cortexa Fund. It acts as the nonprofit arm of Cortexa Therapeutics. Donations to this initiative are tax-deductible, making it a powerful way to support science with impact. Through this, we’re raising $150,000 to launch our first round of in vitro testing on ALS patient-derived motor neurons. So far, we’ve raised $200, with another $40,000 verbally committed, and we need all the help we can get. This early-stage research is crucial—it’s how we’ll prove that calcium-permeable AMPA receptors (CP-AMPARs) are not just present but driving toxicity in ALS motor neurons. We’ll be quantifying receptor expression before, during, and after glutamate stress, validating the mechanism behind our small molecule therapy. Importantly, this research will be widely disseminated and published to help scientific and academic institutions, in support of public benefit.
Gifting Directly to Cortexa Therapeutics (For-Profit) — For those who prefer to support us as a startup, you can contribute directly to Cortexa. These gifts help us move faster on synthesis, IP filings, and operational buildout while preserving founder control and optionality. This will be especially important as we transition beyond our nonprofit-funded in vitro testing into drug development and preclinical validation—turning early data into therapeutic candidates.
Both paths support the same mission. The nonprofit fuels foundational science. The for-profit drives therapy development. Together, they close the loop between discovery and delivery—and both giving options can be accessed through our website.
For the Curious
What are CP-AMPARs? Most AMPA receptors are activated by glutamate, which opens the channel and allows sodium ions to enter the neuron—this helps initiate the electrical signal that allows neurons to fire. But if the GluA2 subunit, of the AMPA receptor, is missing or unedited, they let in calcium instead—turning a normally safe signal into a toxic one. These are calcium-permeable AMPA receptors (CP-AMPARs). They’re rare under normal conditions, but in diseases like ALS, they show up where they shouldn’t—especially on motor neurons.
Excitatory neurons (like pyramidal cells) are the ones that send signals. Inhibitory neurons (like PV or SST interneurons) help shape and constrain those signals. Both can express CP-AMPARs, but their roles are very different. Too many CP-AMPARs on excitatory neurons? You get runaway signaling and cell death. Too few on inhibitory neurons? You lose the brakes. The good news is that, as we've highlighted in previous newsletters, CP-AMPARs on PV interneurons—and likely SST interneurons as well—can be inhibited without disrupting the broader neuronal network. Studies in disease models such as epilepsy and ischemia have shown that selectively blocking CP-AMPARs in these inhibitory populations can preserve circuit function and, in some cases, even stabilize it by reducing excitotoxic leakiness. This gives us a unique therapeutic window: we can dampen pathological excitability in excitatory neurons while maintaining the balance of inhibition—something few strategies can claim. Our therapy aims to restore that balance.
Final Thoughts
We’re not asking for charity. We’re asking for belief—in a better way to treat ALS. If you're reading this and you’ve ever asked how to help: this is it. Every dollar we raise this month goes directly toward proving a mechanism that could reshape ALS therapy.
Again, know someone who’s passionate about science, biotech, or beating ALS? Send this their way. Cortexa isn’t just building a therapy—we’re building a mission-driven movement rooted in urgency, evidence, and the conviction that we can change the game.
Thanks for being part of this.
— Nathan
