Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA
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 infus...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116300300 |
| _version_ | 1818858095905865728 |
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| author | Richard Grondin Pei Ge Qingmin Chen Jessica E Sutherland Zhiming Zhang Don M Gash David K Stiles Gregory R Stewart Dinah W Y Sah William F Kaemmerer |
| author_facet | Richard Grondin Pei Ge Qingmin Chen Jessica E Sutherland Zhiming Zhang Don M Gash David K Stiles Gregory R Stewart Dinah W Y Sah William F Kaemmerer |
| author_sort | Richard Grondin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T08:50:51Z |
| format | Article |
| id | doaj.art-2560f36a757e4533913335385c14852e |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-19T08:50:51Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-2560f36a757e4533913335385c14852e2022-12-21T20:28:44ZengElsevierMolecular Therapy: Nucleic Acids2162-25312015-01-014C10.1038/mtna.2015.20Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNARichard Grondin0Pei Ge1Qingmin Chen2Jessica E Sutherland3Zhiming Zhang4Don M Gash5David K Stiles6Gregory R Stewart7Dinah W Y Sah8William F Kaemmerer9Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USADepartment of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USADepartment of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, USADrug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USADrug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USADrug Delivery R&D, Neuromodulation, Medtronic Inc., Minneapolis, Minnesota, USAOne 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.http://www.sciencedirect.com/science/article/pii/S2162253116300300convection enhanced deliveryHuntington's diseaseputamenrhesussiRNA |
| spellingShingle | Richard Grondin Pei Ge Qingmin Chen Jessica E Sutherland Zhiming Zhang Don M Gash David K Stiles Gregory R Stewart Dinah W Y Sah William F Kaemmerer Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA Molecular Therapy: Nucleic Acids convection enhanced delivery Huntington's disease putamen rhesus siRNA |
| title | Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA |
| title_full | Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA |
| title_fullStr | Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA |
| title_full_unstemmed | Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA |
| title_short | Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA |
| title_sort | onset time and durability of huntingtin suppression in rhesus putamen after direct infusion of antihuntingtin sirna |
| topic | convection enhanced delivery Huntington's disease putamen rhesus siRNA |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116300300 |
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