TY - JOUR
T1 - A modular platform for targeted RNAi therapeutics
AU - Kedmi, Ranit
AU - Veiga, Nuphar
AU - Ramishetti, Srinivas
AU - Goldsmith, Meir
AU - Rosenblum, Daniel
AU - Dammes, Niels
AU - Hazan-Halevy, Inbal
AU - Nahary, Limor
AU - Leviatan-Ben-Arye, Shani
AU - Harlev, Michael
AU - Behlke, Mark
AU - Benhar, Itai
AU - Lieberman, Judy
AU - Peer, Dan
N1 - Funding Information:
This work was supported in part by grants from the Dotan Hemato-oncology Center at Tel Aviv University, by The Leona M. and Harry B. Helmsley Nanotechnology Research Fund, by the Kenneth Rainin Foundation and by the ERC grant LeukoTheranostics (number 647410) awarded to D.P.
Publisher Copyright:
© 2018 The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs 1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting 4-8, their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.
AB - Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs 1-3 (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting 4-8, their clinical translation has not occurred. This is in part because of the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembled modular platform that enables the construction of a theoretically unlimited repertoire of siRNA targeted carriers. The self-assembly of the platform is based on a membrane-anchored lipoprotein that is incorporated into siRNA-loaded lipid nanoparticles that interact with the antibody crystallizable fragment (Fc) domain. We show that a simple switch of eight different mAbs redirects the specific uptake of siRNAs by diverse leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in an inflammatory bowel disease model by targeting colon macrophages to reduce inflammatory symptoms, and in a Mantle Cell Lymphoma xenograft model by targeting cancer cells to induce cell death and improve survival. This modular delivery platform represents a milestone in the development of precision medicine.
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U2 - 10.1038/s41565-017-0043-5
DO - 10.1038/s41565-017-0043-5
M3 - Article
C2 - 29379205
AN - SCOPUS:85041115466
VL - 13
SP - 214
EP - 219
JO - Nature Nanotechnology
JF - Nature Nanotechnology
SN - 1748-3387
IS - 3
ER -