Novel Systemic Delivery of Peptide-Mediated Anti-Sense Oligonucleotides for Dementia with Lewy Bodies

University Of California, San Diego, La Jolla CA

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Abstract

PROJECT SUMMARY/ABSTRACT Neurodegenerative disorders of the aging population are characterized by the progressive accumulation of proteins such as ?-synuclein (?-syn), amyloid beta (Aß) and microtubule associate protein (tau). Misfolded and aggregated ?-syn has been implicated in neurological disorders with Parkinsonism including Dementia with Lewy Body, Parkinson?s disease (PD), and Multiple Systems Atrophy. Accumulation of ?-syn has even been confirmed in over 50% of Alzheimer?s disease (AD). Recent evidence points to a role of ?-syn accumulation in the aggregation of tau and Aß in AD. Thus, regulation of ?-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 ?-syn to reduce expression of ?- 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 ?-syn following intra-peritoneal delivery in an ?-syn tg mouse model of DLB. Then we will examine the ability of the ApoB11:2?-MOe si ?-syn to reduce ?-syn and improve survival of neurons and improve cognitive ability and motor coordination in an ?-syn tg mouse model of DLB. Finally, we will examine the ability of the ApoB11:2?-MOe si ?-syn to reduce the accumulation of ?-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.