| Autor: |
Maja M. Janas, Saeho Chong, Mark K Schlegel, Jason Gilbert, Saket Agarwal, Vasant Jadhav, Dale Gunther, Michelle Jung, Mark Keating, Kelly Wassarman, Shigeo Matsuda, Arlin Rogers, Yongfeng Jiang, Lei Johnson, Elena Castellanos-Rizaldos, Jessica E. Sutherland, Scott Lentini, Urjana Poreci, Klaus Charisse, Jing Li, Anne Kasper, Yesseinia Anglero-Rodriguez, Jeff Rollins, Jing-Tao Wu, Alex Kelin, Sarah Le Blanc Sarah Le Blanc, Diana Cha, Martin E. Maier, Adam Castoreno, Samantha Chigas, Tuyen Nguyen, Muthiah Manoharan, Wendell P Davis, Haiyan Peng, Jayaprakash K. Nair, John Petrulis, Christopher S. Theile, Tyler Chickering, Ivan Zlatev, Tim Racie, Kirk Brown, Christopher R. Brown, Stuart Milstein, Jessica Bombardier, Melissa Mobley, Jeffrey Allen, Raj Maganti, Donald Foster, Kevin Fitzgerald, Jeffrey Kurz, Lauren Blair Woods, Robin McDougall |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
RNA interference (RNAi) therapeutics are a new class of medicines that can address unmet medical needs by silencing disease-causing gene transcripts. While delivery of short interfering RNAs (siRNAs) to hepatocytes has yielded multiple drug approvals, novel delivery solutions are needed to expand the reach of RNAi therapeutics. Here we report that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables efficient silencing in the central nervous system (CNS), eye, and lung of multiple nonclinical species with broad cell type specificity. Intrathecally delivered C16-siRNAs are active across CNS regions and cell types, with sustained silencing for at least three months, which is an especially important outcome considering the challenging dosing route. Similarly, intravitreal and intranasal administration of C16-siRNAs resulted in potent and sustained knockdown in the eye and lung, respectively. Efficient delivery facilitated through C16 conjugation to optimized siRNA designs has enabled candidate selection for investigational human clinical trials assessing therapeutic silencing beyond the liver with infrequent (e.g. bi-annual) dosing. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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