Chronic Treatment Study Using Class C CpG ODN in Aged Non‐Human Primate Model of Sporadic CAA (Saimiri boliviensis boliviensis).

Abstract

AbstractBackgroundTherapeutics that target innate immunity present promising avenues for the treatment of Alzheimer’s disease (AD) neuropathology. Our recently published study using squirrel monkeys (SQMs), a non‐human primate model of sporadic AD with extensive cerebral amyloid angiopathy (CAA), demonstrated that treatment with TLR9 agonist, Class B CpG ODN, safely reduces cognitive deficits and pathological features including parenchymal amyloid deposits, tau pathology, and CAA. Subsequently, we initiated the first chronic treatment study using Class C CpG ODN, and demonstrated its safety and efficacy in eliciting an immune response in a geriatric SQM population. Here, we assess the efficacy of Class C CpG ODN by evaluating plasma biomarkers of neurodegeneration and cognitive status using an innovative computerized testing system.MethodGeriatric SQMs received monthly injections of Class C CpG ODN or saline. Plasma biomarkers of neurodegeneration (NfL, GFAP), neuroinflammation (YKL‐40/CHI3L1), and Aβ40/42 autoantibodies were detected longitudinally using Luminex, SIMOA, or ELISA assays. Furthermore, we have implemented an innovative, touchscreen‐based Automated Cognitive Testing System (ACTS) among socially living SQMs to monitor behavioral changes. Actical® activity monitors recorded general activity parameters (step count, activity count, energy expenditure, and intensity level).ResultPlasma levels of NfL, GFAP, and YKL‐40 were significantly increased in saline‐administered monkeys compared to CpG ODN‐treated cohort. No changes were observed in both treatment groups in general activity parameters. Longitudinal plasma hematological/biochemical parameters and Aβ40/42 IgG and IgM titers revealed no differences between treatment groups, further validating the safety of our immunomodulatory approach. Geriatric SQMs completed the ACTS SHAPE training tasks to a 95% criterion of success within 10 days and are progressing through advanced cognitive tests [Match‐to‐Sample (MTS) and Two‐Choice Discrimination]. Preliminary MTS testing revealed that CpG ODN‐treated group performed with a greater response accuracy than saline controls over the last 1000 trials. Additional biofluid biomarkers and cognitive assessments are being finalized. Longitudinal gene expression profiles (RNA‐seq and NanoString analyses) involved in CpG ODN pathways using PBMCs are underway.ConclusionOur findings enhance the translational value of the SQM model for preclinical research on AD and CAA pathogenesis, as we continue to demonstrate Class C CpG ODN’s safety and therapeutic efficacy in geriatric SQMs.