Liposome-siRNA-peptide complexes cross the blood-brain barrier and significantly decrease PrP on neuronal cells and PrP in infected cell cultures.
BACKGROUND
Recent advances toward an effective therapy for prion diseases employ RNA interference to suppress PrP(C) expression and subsequent prion neuropathology, exploiting the phenomenon that disease severity and progression correlate with host PrP(C) expression levels. However, delivery of lentivirus encoding PrP shRNA has demonstrated only modest efficacy in vivo.


RESULTS
Here we describe a new siRNA delivery system incorporating a small peptide that binds siRNA and acetylcholine receptors (AchRs), acting as a molecular messenger for delivery to neurons, and cationic liposomes that protect siRNA-peptide complexes from serum degradation.


CONCLUSIONS
Liposome-siRNA-peptide complexes (LSPCs) delivered PrP siRNA specifically to AchR-expressing cells, suppressed PrP(C) expression and eliminated PrP(RES) formation in vitro. LSPCs injected intravenously into mice resisted serum degradation and delivered PrP siRNA throughout the brain to AchR and PrP(C)-expressing neurons. These data promote LSPCs as effective vehicles for delivery of PrP and other siRNAs specifically to neurons to treat prion and other neuropathological diseases.
Pulford
Bruce
B
Department of Microbiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
Reim
Natalia
N
Bell
Aimee
A
Veatch
Jessica
J
Forster
Genevieve
G
Bender
Heather
H
Meyerett
Crystal
C
Hafeman
Scott
S
Michel
Brady
B
Johnson
Theodore
T
Wyckoff
A Christy
AC
Miele
Gino
G
Julius
Christian
C
Kranich
Jan
J
Schenkel
Alan
A
Dow
Steven
S
Zabel
Mark D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier; D002460:Cell Line; D002478:Cells, Cultured; D008081:Liposomes; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000493:pharmacokinetics*
D008081:Liposomes; D011328:Prions; D034741:RNA, Small Interfering