Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates |
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| Authors: | Christopher R Brown Swati Gupta June Qin Timothy Racie Guo He Scott Lentini Ryan Malone Mikyung Yu Shigeo Matsuda Svetlana Shulga-Morskaya Anil V Nair Christopher S Theile Karyn Schmidt Azar Shahraz Varun Goel Rubina G Parmar Ivan Zlatev Mark K Schlegel Jayaprakash K Nair Muthusamy Jayaraman Muthiah Manoharan Dennis Brown Martin A Maier Vasant Jadhav |
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| Institution: | Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA;MGH Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA |
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| Abstract: | One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly generated Argonaute 2 protein complexes weeks after dosing, enabling continuous RNAi activity over time. Identical siRNAs delivered in lipid nanoparticles or as GalNAc conjugates were dose-adjusted to achieve similar knockdown, but only GalNAc–siRNAs supported an extended duration of activity, illustrating the importance of receptor-mediated siRNA trafficking in the process. Taken together, we provide several lines of evidence that acidic intracellular compartments serve as a long-term depot for GalNAc–siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo. |
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