Pridopidine exerts neuroprotective effects through the activation of the Sigma-1 receptor (S1R) by modulating ER stress in iPSC-derived neural progeni

Topic:

Pre-Clinical Research

Poster Number: 192 M

Author(s):

Nils Confer, PhD, MBA, Prilenia, May Meltzer, PhD, Prilenia Therapeutics, Randal Hand, PhD, Prilenia Therapeutics, Andrew Tan, PhD, Prilenia Therapeutics, Maya Shefler, Department of Biotechnology Engineering, Ben Gurion University, Noam Tzuri, Department of Biotechnology Engineering, Ben Gurion University, Rachel G. Lichtenstein, PhD, Department of Biotechnology Engineering, Ben Gurion University, Michal Geva, PhD, Prilenia Therapeutics, Michael R. Hayden, MB, ChB, PhD, FRCP(C), FRSC, Prilenia Therapeutics; Center for Molecular Medicine and Therapeutics University of British Columbia

Background: Pridopidine is a selective S1R agonist in clinical development for amyotrophic lateral sclerosis (ALS) and Huntington’s Disease. The S1R is a compelling therapeutic target as it is expressed in areas in the central nervous system relevant to ALS, and mutations in S1R are associated with rare forms of ALS. In the Ph2 HEALEY ALS Platform Trial, pridopidine demonstrated benefits in a subgroup of patients meeting definite or probable ALS by El Escorial criteria, early in their disease (<18 months from symptom onset). In preclinical studies, pridopidine ameliorates key features of ALS in SOD1G93A mice, increasing body weight and muscle fiber, reducing toxic SOD1 aggregates, and improving motor coordination. In SOD1G93A motor neurons , pridopidine improves synaptic function, BDNF transport, and survival. Endoplasmic reticulum (ER) stress, an early hallmark of ALS, activates the unfolded protein response (UPR) through key mediators, including the upregulation of the proteins BiP and CHOP. Objective: To investigate pridopidine’s ability to modulate ER stress in an in vitro model of ALS. Methods: Neural progenitor cells (NPCs) were generated from induced pluripotent stem cells (iPSCs) derived from a sporadic human ALS patient. Following ER stress induction with tunicamycin, levels of UPR markers BiP and CHOP were evaluated by flow cytometry and immunochemistry, and cell viability assessed by flow cytometry. Results: Pridopidine significantly reduced expression of UPR markers (BiP: 72%, p<0.0001; CHOP: 52%, p<0.0001). This reduction correlated with improved cell viability and growth (50% increase, p<0.0001) of pridopidine-treated NPCs compared to control NPCs. The neuroprotective effects of pridopidine are S1R-dependent as inhibition by the S1R antagonist NE-100 attenuated pridopidine’s neuroprotective effects. Conclusion: These findings highlight pridopidine’s potential to enhance neuronal survival by mitigating ER stress, a key driver of ALS pathology. Given its ability to modulate fundamental disease mechanisms, pridopidine represents a promising therapeutic strategy for ALS.