Widespread suppression of huntingtin with convection-enhanced delivery of siRNA

David K. Stiles, Zhiming Zhang, Pei Ge, Brian Nelson, Richard Grondin, Yi Ai, Peter Hardy, Peter T. Nelson, Andrei P. Guzaev, Mark T. Butt, Klaus Charisse, Verbena Kosovrasti, Lubomir Tchangov, Michael Meys, Martin Maier, Lubomir Nechev, Muthiah Manoharan, William F. Kaemmerer, Douglas Gwost, Gregory R. StewartDon M. Gash, Dinah W.Y. Sah

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Huntington's disease is an autosomal dominant neurodegenerative disease caused by a toxic gain of function mutation in the huntingtin gene (Htt). Silencing of Htt with RNA interference using direct CNS delivery in rodent models of Huntington's disease has been shown to reduce pathology and promote neuronal recovery. A key translational step for this approach is extension to the larger non-human primate brain, achieving sufficient distribution of small interfering RNA targeting Htt (siHtt) and levels of Htt suppression that may have therapeutic benefit. We evaluated the potential for convection enhanced delivery (CED) of siHtt to provide widespread and robust suppression of Htt in nonhuman primates. siHtt was infused continuously for 7 or 28. days into the nonhuman primate putamen to analyze effects of infusion rate and drug concentration on the volume of effective suppression. Distribution of radiolabeled siHtt and Htt suppression were quantified by autoradiography and PCR, respectively, in tissue punches. Histopathology was evaluated and Htt suppression was also visualized in animals treated for 28. days. Seven days of CED led to widespread distribution of siHtt and significant Htt silencing throughout the nonhuman primate striatum in an infusion rate and dose dependent manner. Htt suppression at therapeutic dose levels was well tolerated by the brain. A model developed from these results predicts that continuous CED of siHtt can achieve significant coverage of the striatum of Huntington's disease patients. These findings suggest that this approach may provide an important therapeutic strategy for treating Huntington's disease.

Original languageEnglish
Pages (from-to)463-471
Number of pages9
JournalExperimental Neurology
Issue number1
StatePublished - Jan 2012

Bibliographical note

Funding Information:
The research was supported by grants from Alnylam Pharmaceuticals and Medtronic Neuromodulation , and some of the authors are employees and shareholders of these companies. We thank Lauren Lesser and Maryellen Livingston for graphics assistance, and Mike Kaytor and QPS Pharmaceutical Services for technical assistance.


  • Convection enhanced delivery
  • Huntington's disease
  • Putamen
  • Site-specific delivery
  • Striatum

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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