Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9. doi: 10.1073/pnas.0708285104. Epub 2007 Oct 16.


Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the huntingtin (Htt) gene. HD is autosomal dominant and, in theory, amenable to therapeutic RNA silencing. We introduced cholesterol-conjugated small interfering RNA duplexes (cc-siRNA) targeting human Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 CAG) Htt cDNA encoding huntingtin (Htt) 1-400. Adeno-associated virus delivery to striatum and overlying cortex of the mutant Htt gene, but not the wild type, produced neuropathology and motor deficits. Treatment with cc-siRNA-Htt in mice with mutant Htt prolonged survival of striatal neurons, reduced neuropil aggregates, diminished inclusion size, and lowered the frequency of clasping and footslips on balance beam. cc-siRNA-Htt was designed to target human wild-type and mutant Htt and decreased levels of both in the striatum. Our findings indicate that a single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology*
  • Cholesterol / metabolism
  • Dependovirus
  • Disease Models, Animal
  • Gene Silencing*
  • Genetic Therapy*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / pathology
  • Huntington Disease / therapy
  • Injections
  • Intranuclear Inclusion Bodies / drug effects
  • Intranuclear Inclusion Bodies / pathology
  • Intranuclear Inclusion Bodies / ultrastructure
  • Mice
  • Motor Neuron Disease / pathology
  • Mutant Proteins / antagonists & inhibitors*
  • Neostriatum / drug effects
  • Neostriatum / pathology*
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / immunology
  • Neurons / pathology
  • Neurons / ultrastructure
  • Neuropil Threads / drug effects
  • Neuropil Threads / ultrastructure
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / immunology
  • RNA, Small Interfering / pharmacology*


  • HTT protein, human
  • Huntingtin Protein
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Cholesterol