Objective:

To evaluate the efficacy of RTX-117 in the treatment of neurodegenerative diseases.

Background:

The integrated stress response (ISR) is a conserved translational and transcriptional program that enables the cell to return to homeostasis in response to a variety of stressors in the cytoplasm and endoplasmic reticulum. Unresolved chronic ISR activation can lead to cellular apoptosis and is a hallmark of a number of neurodegenerative diseases including vanishing white matter (VWM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). RTX-117 is a small molecule inhibitor of the ISR which is orally bioavailable and highly brain penetrant, suggesting its utility in treating ISR-related pathologies.

Design/Methods:

We evaluated RTX-117 in several in vitro cellular models including induced pluripotent stem cell (iPSC)-derived motor neurons, and in vivo studies in VWM and ALS mouse models. A Phase 1 study in healthy volunteers will be initiated in early 2025.

Results:

RTX-117 is a potent inhibitor of the ISR pathway as measured by the suppression of an ISR-mediated gene signature in vitro and in vivo. In the VWM in vivo study, RTX-117 improved motor function and body weight gain in treated mice at the low dose of 0.1 mg/Kg. Data from other studies will also be presented.

Conclusions:

RTX-117 is a promising therapeutic option for neurodegenerative diseases where chronic ISR is implicated.