Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP = 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

Automated summary

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes voluntary muscle function loss and often leads to death within 2-5 years. Respiratory vital capacity (VC) measurements can predict survival, and a study has found a potential therapeutic approach for controlling VC loss in ALS patients by regulating the innate immune system. Patients with high levels of plasma CRP showed a slower decline in VC compared to placebo, while those with low CRP showed no response. This study provides the first evidence linking biomarker-confirmed regulation of the innate immune system with a potential treatment for VC loss in ALS patients.