Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates

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, and Vasant Jadhav

Nucleic Acids Research, gkaa670,

Brown et al. provide several lines of evidence that acidic intracellular compartments serve as a longterm depot for GalNAc-siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo. Essentially, this serves as a living slow release mechanism that provides compound in the cytosol gradually, thereby enabling long term control of gene expression . This work explains the biological origins of the long duration of effect, and could improve strategies for drug development, clinical trial design, and long-term administration of siRNA drugs to patients.

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