Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis.
The primary cause of Huntington's disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebrospinal fluid of symptomatic HD mouse models not only delays disease progression but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild-type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into nonhuman primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis.
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Holly B
HB
Kordasiewicz
Lisa M
LM
Stanek
Edward V
EV
Wancewicz
Curt
C
Mazur
Melissa M
MM
McAlonis
Kimberly A
KA
Pytel
Jonathan W
JW
Artates
Andreas
A
Weiss
Seng H
SH
Cheng
Lamya S
LS
Shihabuddin
Gene
G
Hung
C Frank
CF
Bennett
Don W
DW
Cleveland
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D060186:Infusions, Spinal; D008253:Macaca mulatta; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D013995:Time; D016896:Treatment Outcome
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense