Cortexa Weekly— June 1st 2025
Cortexa Progress
Protecting the Blueprint
Big milestone this week: we filed our provisional patent covering our dual-targeted approach to ALS via CP-AMPAR and NR2B-NMDAR blockade. This locks in our priority date and gives us 12 months to refine, test, and expand on the claims before filing the non-provisional. We also wrapped up the trademark filing for Cortexa Therapeutics. It feels good to have our name, mission, and science starting to take form not just in the lab, but in the legal record.
These filings aren't just paperwork. They're a commitment: to our ideas, to the patients we want to help, and to the mission of bringing a first-in-class therapy forward. Now it's about backing that commitment with data.
Research Spotlight
Study Title: Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons
Journal: EMBO Molecular Medicine (2013)
URL: https://pubmed.ncbi.nlm.nih.gov/24115583/
RNA Editing, ALS, and the Return of ADAR2
Over the last few months, I’ve looked into and have referenced a fascinating study from Japan where researchers used an AAV9-delivered ADAR2 gene therapy to rescue motor neuron function in ALS models. ADAR2 is the RNA editor that converts glutamine (Q) to arginine (R) at the Q/R site of the GluA2 AMPA receptor subunit. Without this edit, GluA2 becomes calcium-permeable, turning AMPA receptors into calcium floodgates and setting off excitotoxic cascades.
In ALS, ADAR2 is selectively downregulated in motor neurons. The Japanese team delivered ADAR2 via AAV9 vectors under the synapsin promoter to restore Q/R site editing in spinal motor neurons. The result? Reduced TDP-43 pathology, improved survival, and restoration of normal calcium impermeability. Even more impressively, their therapy reversed disease phenotypes after symptom onset.
This aligns beautifully with our model at Cortexa: calcium-permeable AMPA receptors (CP-AMPARs) are central to disease progression. Whether through faulty editing (like loss of ADAR2) or TARP dysregulation, the result is the same: calcium overload, mitochondrial damage, and motor neuron death. The Japanese study validates the upstream hypothesis we've been building around for months.
While we're not pursuing gene therapy ourselves, this work shows that fixing GluA2 permeability can actually reverse ALS pathology, not just slow it. That’s huge. It’s not a stretch to imagine a future where our receptor-targeted small molecules work synergistically with gene therapies that restore RNA editing. Two complementary tools—one targeting the hardware, the other the firmware.
What I’m Thinking About
Blueprints, Floodgates, and Fixing the Firmware
Between locking in our patent and reading about the ADAR2 rescue study, one thing is clear: ALS is, in many ways, a disease of bad code and broken gates.
If your motor neurons are computers, GluA2 is the firewall. When that firewall fails—either because ADAR2 stopped editing the code or because the receptors are trafficked without GluA2—you get catastrophic calcium leakage. Every signal turns toxic. Our job at Cortexa is to patch the leak.
That’s why I’m so encouraged by this week’s science. The Japanese group didn’t just show that GluA2 editing matters—they showed it can be fixed after the disease starts. That gives every one of us working on ALS something we rarely get: hope grounded in mechanism.
Join the Movement
More next week. If someone in your life cares about science, startups, or solving ALS, pass this along. Cortexa isn’t just a company—it’s a movement driven by urgency, backed by evidence, and powered by people who believe we can do better. Every step we take is one step closer to tipping the balance.
Whether you're here for the science or the mission, thanks for being in it with us.
