Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.

Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1G93A mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl+ phagocytic-module fraction increased while the Dectin-1+ inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.