Cortexa Weekly— October 7th 2025
Cortexa Progress
I want to begin by apologizing for the hiatus since my last newsletter. During this time, we have been diligently advancing our research. I’m excited to share that we have officially begun our Phase 1 studies with our CRO partner, Concept Life Sciences, based in Edinburgh, Scotland. This study focuses on TARDBP (TDP-43) mutations, which drive the mislocalization of TDP-43 protein — a hallmark of nearly all sporadic ALS cases. Although these mutations are familial in origin, they most closely resemble the protein pathology seen in sporadic ALS.
To begin this research, we purchased several million induced pluripotent stem cells (iPSCs) from Fujifilm and are now differentiating them into motor neurons for detailed study. In parallel, we have initiated synthesis of our first three proprietary compounds with a separate CRO, Eurofins. We expect synthesis to be complete within the next four weeks, after which we will begin testing these compounds directly in our iPSC-derived motor neuron models in Phase 2.
Research Pipeline Progress
Phase 1 Studies: Ongoing with Concept Life Sciences, targeting TARDBP mutations for TDP-43 mislocalization. Focusing on observing and quantifying proteins to further validate our target.
iPSC Models: Large-scale cultures underway using two separate mutations of Fujifilm-sourced lines, enabling high-throughput testing.
Compound Synthesis: Three proprietary molecules are currently in production, with an anticipated completion in four weeks.
Looking Ahead
By December, we anticipate having solid data to support our target by quantifying key protein subunits of ionotropic receptors, along with enzymes such as ADAR2. These findings will provide the foundation for our Phase 2 study. At that point, the next major milestone will be the application of our proprietary compounds to iPSC-derived motor neurons, allowing us to evaluate their interaction and, eventually whether our therapeutic strategy can stabilize TDP-43 pathology and improve neuronal survival. The outcome of this work will be pivotal in shaping our preclinical program and positioning us for future venture capital funding.
Recent Studies & How They Inform Our Strategy
Emerging clinical and preclinical work continues to validate hyperexcitability and calcium overload as central drivers of motor neuron injury in ALS. Studies demonstrating early cortical and spinal hyperexcitability, TDP-43–linked dysregulation of RNA/protein homeostasis, and increased calcium-permeable receptor activity all align with our focus on dampening pathological calcium entry and restoring electrophysiological balance.
Reflection: QurAlis QRL‑101 (Potassium Channel Opener)
QRL‑101 is designed to open voltage‑gated potassium channels (e.g., Kv7/KCNQ), stabilizing the neuronal membrane and reducing repetitive firing. By lowering hyperexcitability, a potassium channel opener can indirectly decrease downstream calcium influx and excitotoxic stress. This approach is conceptually aligned with the excitotoxicity model: fewer pathologic action potentials → reduced glutamate release and NMDA/AMPA activation → less intracellular calcium burden.
How this relates to our strategy:
Complementary mechanisms: While QRL‑101 targets membrane excitability upstream, our program aims to directly limit calcium entry at the receptor level (ionotropic glutamate receptors). Both approaches pursue the same end state: lower intracellular calcium and improved neuronal resilience.
Translatability and biomarkers: We anticipate convergence in readouts such as neuronal survival, electrophysiology (MEP/EMG measures of hyperexcitability), and fluid biomarkers (e.g., NfL). This creates opportunities for combinatorial or sequential strategies in future studies.
QurAlis has advanced QRL‑101 into Phase 1 clinical trials at UMC Utrecht in the Netherlands, reflecting tangible clinical momentum in this area. This is a small molecule therapy, and I am watching this development closely.
Thank You for Your Support
So many of you have donated already, and I could not be more thankful. None of this progress would be possible without the support of our growing community. Every step brings us closer to transformative therapies for ALS, and I remain deeply grateful for those who believe in our mission.
Stay tuned for more updates as we move into this exciting next phase of research.
— Nathan
