TY - JOUR
T1 - Onset time and durability of huntingtin suppression in rhesus putamen after direct infusion of antihuntingtin siRNA
AU - Grondin, Richard
AU - Ge, Pei
AU - Chen, Qingmin
AU - Sutherland, Jessica E.
AU - Zhang, Zhiming
AU - Gash, Don M.
AU - Stiles, David K.
AU - Stewart, Gregory R.
AU - Sah, Dinah W.Y.
AU - Kaemmerer, William F.
N1 - Publisher Copyright:
© 2015 The American Society of Gene & Cell Therapy All rights reserved.
PY - 2015/6
Y1 - 2015/6
N2 - 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.
AB - 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.
KW - Convection enhanced delivery
KW - Huntington's disease
KW - Putamen
KW - Rhesus
KW - SiRNA
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U2 - 10.1038/mtna.2015.20
DO - 10.1038/mtna.2015.20
M3 - Article
AN - SCOPUS:84943425235
VL - 4
SP - e245
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
IS - 6
M1 - e245
ER -