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.

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Published in Molecular Therapy—Nucleic Acids, v. 4, article e245, p. 1-13.

© 2015 The American Society of Gene & Cell Therapy

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

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CHDI Foundation, Inc., a privately-funded not-for-profit biomedical research organization exclusively dedicated to developing therapies that slow the progression of Huntington disease, provided financial support for this study under a research agreement between CHDI Foundation, Medtronic, and Alnylam Pharmaceuticals. At the time this study was conducted, Pei Ge, Qingmin Chen, Jessica Sutherland, and Dinah Sah were salaried employees of Alnylam Pharmaceuticals, and David Stiles, Gregory Stewart and William Kaemmerer were salaried employees of Medtronic, Inc.

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