Advanced Preclinical Testing of NKCC1 Inhibitors to Support Phase 2 Clinical Trials in Fragile X
Laura Cancedda, PhD
Principal Investigator
Dounia Chater, PhD
FRAXA Postdoctoral Fellow
Italian Institute of Technology (IIT)
Genoa, Italy
2025-2026 Grant Funding: $100,000
With support from the Autism Science Foundation
Summary
This project is testing a new treatment that aims to improve brain balance in Fragile X syndrome without the side effects seen with older drugs. The compound targets a pathway linked to the brain’s overactivity and has already completed early safety testing in humans. With additional preclinical work, this research could help move a non-diuretic, more precise therapy for Fragile X into Phase 2 clinical trials.
The Science
In Fragile X syndrome, brain cells often struggle to maintain the normal balance between excitation and inhibition. This imbalance can make the brain overly reactive and contribute to symptoms such as seizures, sensory overload, and learning difficulties. One pathway involved in this process is the regulation of chloride ions inside neurons, controlled in part by the proteins NKCC1 and KCC2.
A previous drug candidate, Bumetanide, blocks NKCC1 and showed early promise in autism and Fragile X studies. However, because it is a strong diuretic, it could only be used at very low doses. To address this limitation, Dr. Laura Cancedda’s team has developed a new compound, ARN23746 (IAMA-6), that selectively inhibits NKCC1 without causing diuretic side effects. The compound has been licensed to the pharmaceutical company IAMA Therapeutics, and early research in mouse models of Fragile X and other neurological conditions indicates that it may help restore more typical patterns of brain activity. It has also completed Phase I safety testing in healthy volunteers.
With support from FRAXA and the Autism Science Foundation, the researchers will:
- Investigate how ARN23746 affects molecular pathways that influence brain function
- Conduct additional preclinical safety and efficacy studies in Fragile X mouse models, an important step toward clinical testing
- Examine potential differences in symptoms and treatment responses between males and females
If successful, this work could help prepare a non-diuretic, brain-targeted NKCC1 inhibitor for advancement into Phase 2 clinical trials.