Modulating ApoE with Tissue Specific siRNAs in Alzheimer’s Disease

Among many putative genetic risk variations reported to date, the ApoE4 allele remains the most common genetic risk factor for late-onset AD, and is associated with both an increase in incidence and a decrease in age of clinical onset. The majority of ApoE is produced in the: 1) central nervous system (CNS) by astrocytes to transport lipids between cells and modulate the inflammatory response; and 2) liver, where it facilitates lipid uptake into peripheral tissues via low-density lipoprotein (LDL) receptors. Consistent with its dual roles, genetic knockout of ApoE increases the risk for atherosclerosis, but it also dramatically improves AD phenotypes in mouse models. Antisense oligonucleotide (ASO) based modulation of CNS ApoE has only marginal effects on AD phenotypes, suggesting that post-embryonic silencing of ApoE is not a viable therapeutic strategy. However, the recent development of novel CNS siRNA chemical structures enables widespread distribution and potent target silencing throughout the brain. Using this technology, we demonstrate that liver and brain ApoE pools are spatially and functionally distinct, and that complete silencing of brain, not liver, ApoE results in robust reduction of amyloid plaque formation, without impacting systemic cholesterol. Furthermore, RNAseq analysis shows minimal off target effects of the siRNAs and identifies immune modulation and metabolic alterations as potential mechanisms behind ApoE’s role in plaque formation and clearance. Moving forward, these results build upon the rationale to modulate ApoE expression and provide the technology necessary to further evaluate the impact ApoE silencing in AD and other neurodegenerative disease