PROJECT SUMMARY/ABSTRACT Neurodegenerative disorders of the aging population are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn), amyloid beta (Aß) and microtubule associate protein (tau). Misfolded and aggregated α-syn has been implicated in neurological disorders with Parkinsonism including Dementia with Lewy Body, Parkinson’s disease (PD), and Multiple Systems Atrophy. Accumulation of α-syn has even been confirmed in over 50% of Alzheimer’s disease (AD). Recent evidence points to a role of α-syn accumulation in the aggregation of tau and Aß in AD. Thus, regulation of α-syn expression may be crucial to the therapeutic control of numerous neurodegenerative diseases. Short interfering RNA molecules (siRNA) can bind specifically to target RNAs and deliver them for degradation; however, RNA molecules do not cross the blood- brain barrier so the only method for delivery is repeat intra-thecal injections. We recently developed a peptide (ApoB11) that binds oligonucleotides for transport across the blood-brain barrier following systemic administration. Using this peptide, we showed that we can deliver a si α-syn to reduce expression of α- synuclein in a mouse. We recently converted the ribonucleotide backbone of this siRNA to a 2’-MOe anti-sense oligonucleotide to increase half-life and affinity to the mRNA target. We plan to examine the pharmacokinetics and toxicology of systemic ApoB11:2’-MOe si α-syn following intra-peritoneal delivery in an α-syn tg mouse model of DLB. Then we will examine the ability of the ApoB11:2’-MOe si α-syn to reduce α-syn and improve survival of neurons and improve cognitive ability and motor coordination in an α-syn tg mouse model of DLB. Finally, we will examine the ability of the ApoB11:2’-MOe si α-syn to reduce the accumulation of α-syn in an in vitro model of human DLB neurons derived from iPSC cells in a blood-brain barrier model. We believe this may represent a new method of therapeutic delivery for DLB and other neurological disorders.