title: Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA.
abstract: One possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied the suppression of huntingtin mRNA achievable with short infusion times, and investigated how long suppression may persist after infusion ceases. Rhesus monkeys received 3 days of infusion of Magnevist into the putamen to confirm catheter patency and fluid distribution. After a 1-week washout period, monkeys received radiolabeled siRNA targeting huntingtin. After 1 or 3 days of siRNA delivery, monkeys were either terminated, or their pumps were shut off and they were terminated 10 or 24 days later. Results indicate that the onset of huntingtin mRNA suppression in the rhesus putamen occurs rapidly, achieving a plateau throughout the putamen within 4 days. Conversely, loss of huntingtin suppression progresses slowly, persisting an estimated 27-39 days in the putamen and surrounding white matter. These findings indicate the rapid onset and durability of siRNA-mediated target gene suppression observed in other organs also occurs in the brain, and support the use of episodic delivery of siRNA into the brain for treatment of Huntington's disease and possibly other neurodegenerative diseases.
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Grondin
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Sutherland
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Don M
authors.initials: DM
authors.lastname: Gash
authors.affiliation: Drug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Stiles
authors.affiliation: Drug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Stewart
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
authors.affiliation: Drug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Kaemmerer