Antisense oligonucleotide therapy for neurodegenerative disease.
Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.
Smith
Richard A
RA
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA.
Miller
Timothy M
TM
Yamanaka
Koji
K
Monia
Brett P
BP
Condon
Thomas P
TP
Hung
Gene
G
Lobsiger
Christian S
CS
Ward
Chris M
CM
McAlonis-Downes
Melissa
M
Wei
Hongbing
H
Wancewicz
Ed V
EV
Bennett
C Frank
CF
Cleveland
Don W
DW
D000818:Animals; D001483:Base Sequence; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D008253:Macaca mulatta; D016472:Motor Neuron Disease / Q000201:enzymology; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016276:Ventricular Function
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1