RRC ID 60828
Author Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, Baba K, Nagata T, Yokota T, Tsuda H, Obika S, Mochizuki H.
Title Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson's disease.
Journal Sci Rep
Abstract Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. A characteristic pathological feature of PD is cytoplasmic accumulation of α-synuclein (SNCA) protein. Multiplication of the SNCA gene in familial PD and pathological accumulation of SNCA protein during progression of sporadic PD suggest that increased SNCA protein levels increase the risk of PD. Thus, reducing SNCA expression levels could delay PD onset or modify the disease course. For efficient knock down, we designed and synthesized an amido-bridged nucleic acids (AmNA)-modified antisense oligonucleotide (ASO) that targeted SNCA with improved stability and cellular uptake in vivo. AmNA-ASO efficiently downregulated SNCA at both the mRNA and protein level in vitro and in vivo. Notably, AmNA-ASO was efficiently delivered into the mouse brain by intracerebroventricular injection without the aid of additional chemicals. Furthermore, administration of AmNA-ASO ameliorated neurological defects in PD model mice expressing human wild type SNCA. Taken together, these findings suggest that AmNA-ASO is a promising therapeutic strategy for SNCA-associated pathology in PD.
Volume 9(1)
Pages 7567
Published 2019-5-21
DOI 10.1038/s41598-019-43772-9
PII 10.1038/s41598-019-43772-9
PMID 31110191
PMC PMC6527855
MeSH Animals HEK293 Cells Humans Mice Mice, Inbred C57BL Mice, Inbred DBA Oligonucleotides / genetics Parkinson Disease / therapy* RNA, Antisense / genetics* RNA, Antisense / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism RNAi Therapeutics / methods* alpha-Synuclein / genetics* alpha-Synuclein / metabolism
IF 4.011
Times Cited 4
Mice RBRC02830