title: Widespread suppression of huntingtin with convection-enhanced delivery of siRNA.
abstract: 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.
authors: Medtronic Neuromodulation, Medtronic, Minneapolis, MN 55432, USA.
authors: David K
authors: DK
authors: Stiles
authors: Zhiming
authors: Z
authors: Zhang
authors: Pei
authors: P
authors: Ge
authors: Brian
authors: B
authors: Nelson
authors: Richard
authors: R
authors: Grondin
authors: Yi
authors: Y
authors: Ai
authors: Peter
authors: P
authors: Hardy
authors: Peter T
authors: PT
authors: Nelson
authors: Andrei P
authors: AP
authors: Guzaev
authors: Mark T
authors: MT
authors: Butt
authors: Klaus
authors: K
authors: Charisse
authors: Verbena
authors: V
authors: Kosovrasti
authors: Lubomir
authors: L
authors: Tchangov
authors: Michael
authors: M
authors: Meys
authors: Martin
authors: M
authors: Maier
authors: Lubomir
authors: L
authors: Nechev
authors: Muthiah
authors: M
authors: Manoharan
authors: William F
authors: WF
authors: Kaemmerer
authors: Douglas
authors: D
authors: Gwost
authors: Gregory R
authors: GR
authors: Stewart
authors: Don M
authors: DM
authors: Gash
authors: Dinah W Y
authors: DW
authors: Sah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002247:Carbon Isotopes / Q000378:metabolism; D018481:Convection; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D000071058:Huntingtin Protein; D008253:Macaca mulatta; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D011877:Radionuclide Imaging; D013997:Time Factors
chemical_list: D002247:Carbon Isotopes; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering