[HTML][HTML] Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson's disease

T Uehara, CJ Choong, M Nakamori, H Hayakawa… - Scientific reports, 2019 - nature.com
T Uehara, CJ Choong, M Nakamori, H Hayakawa, K Nishiyama, Y Kasahara, K Baba…
Scientific reports, 2019nature.com
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 …
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.
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