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

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,751,085

## Abstract

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.

## Key facts

- **NIH application ID:** 10186335
- **Project number:** 1RF1AG072053-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert Rissman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,751,085
- **Award type:** 1
- **Project period:** 2021-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186335

## Citation

> US National Institutes of Health, RePORTER application 10186335, Novel Systemic Delivery of Peptide-Mediated Anti-Sense Oligonucleotides for Dementia with Lewy Bodies (1RF1AG072053-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186335. Licensed CC0.

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