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 o...

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Bibliographic Details
Published in:	Neuron (Cambridge, Mass.) Vol. 74; no. 6; pp. 1031 - 1044
Main Authors:	Kordasiewicz, Holly B., Stanek, Lisa M., Wancewicz, Edward V., Mazur, Curt, McAlonis, Melissa M., Pytel, Kimberly A., Artates, Jonathan W., Weiss, Andreas, Cheng, Seng H., Shihabuddin, Lamya S., Hung, Gene, Bennett, C. Frank, Cleveland, Don W.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 21-06-2012 Elsevier Limited
Subjects:	Animals Corpus Striatum - metabolism Corpus Striatum - pathology Disease Models, Animal Disease Progression Huntingtin Protein Huntington Disease - genetics Huntington Disease - pathology Huntington Disease - therapy Huntingtons disease Infusions, Spinal Macaca mulatta Mice Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - biosynthesis Nerve Tissue Proteins - genetics Neurons - metabolism Neurons - pathology Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - biosynthesis Nuclear Proteins - genetics Oligodeoxyribonucleotides, Antisense - administration & dosage Oligodeoxyribonucleotides, Antisense - therapeutic use Pharmaceuticals Proteins Rodents Time Treatment Outcome
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Summary:	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. ► ASOs suppress huntingtin throughout the rodent and nonhuman primate CNS ► ASO therapy reverses disease, prevents brain loss, and promotes survival in HD models ► ASO-mediated disease reversal persists for longer than huntingtin suppression ► Suppression of mutant huntingtin reverses disease independent of wild-type levels Kordasiewicz et al. establish antisense oligonucleotide infusion as a potential therapy for Huntington's disease. Suppression of huntingtin synthesis is achieved throughout the rodent and nonhuman primate CNS, producing sustained phenotypic reversal that extends beyond the duration of huntingtin suppression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0896-6273 1097-4199
DOI:	10.1016/j.neuron.2012.05.009