First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects

<p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with immune dysregulation. Based on the robust therapeutic effect and immunoregulatory capability of gp96 administration in the SOD1G93A mouse model, we conducted a prospective one-arm, open-label, proof-of-concept clinical trial in Hainan, China. High-dose gp96 was well tolerated in all 10 enrolled patients with ALS, and pronouncedly reduced the levels of inflammatory immune cells—CD14⁺ monocytes, NK cells, and CD4⁺ and CD8⁺ effector T cells—to levels comparable to those seen in healthy individuals. Treatment with gp96 also enhanced the suppressive function of Tregs and promoted the expansion of both activated Tregs and the CD38⁺LAG3⁺CXCR3^hiCD27^hi Treg subset. All participants experienced a slower decline in ALSFRS-R scores during the first 16 weeks post-treatment, and this slower decline was sustained in 40% (4/10) of patients at the end of follow-up in week 72. Treatment duration and Treg activation were positively correlated with the efficacy of gp96 treatment in alleviating the disease progression rate. These preliminary results emphasize the importance of the early identification of fast-progressing ALS patients and the need for long-term treatment. Our findings support further evaluation of gp96 as an immunomodulatory agent against ALS in randomized controlled trials with standardized outcome measures.</p>