P2–410: Innate immunity stimulation via TLR9 in a non‐human primate model of sporadic cerebral amyloid angiopathy

Abstract

Immunomodulation has shown great promise as an Alzheimer's disease (AD) therapy but major limitations must be overcome, such as the need for effectively reducing cerebral amyloid angiopathy (CAA), without associated hemorrhages. CAA is a common feature in AD and cognitively normal elderly individuals. Our initial findings indicate that stimulation of innate immunity with CpG ODN appears to be an effective means of reducing vascular amyloid without inducing toxicity in AD mouse models. We are currently testing our approach in a well characterized non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis), which share numerous biological similarities with humans. Varying doses of the class B CpG ODN preparation containing the primate specific immunostimulatory sequence were administered in young monkeys by a subcutaneous route (s.c.). The most effective and non-toxic dosage described in young animals was selected for our long term studies in the older animals (with expected CAA deposits). During the treatment, primates were closely monitored for signs of toxicity. The peripheral cytokine responses were determined in PBMC supernatants and plasma from control and treated monkeys at selected time points. In addition, the performances on cognitive tests are being compared between our aged and young squirrel monkeys. We have shown that a TLR9 agonist prevented short-term memory deficits in Tg-SwDI mice, a model with extensive CAA. CpG ODN treatment led to a reduction of CAA in the absence of microhemorrhages and increased inflammation. Transgenic models are ideal for initial screening of a potential therapy but prior to clinical trials it is imperative to perform studies in non-human primates, which are a more biologically proximate model to humans. Short duration safety and efficacy assessment studies were first performed in young monkeys. Characterization of immune responses and evaluation of cognitive function and working memory in our monkeys is currently in progress. Assessment of the therapeutic potential of CpG ODN in aged squirrel monkeys, at a point where CAA is already present, is on-going. Overall, the studies described here provide a basis for potential future clinical trials of TLR9 stimulation with CpG ODNs to ameliorate AD related pathology in humans.