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OtherMinireview

The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man

Saeho Chong, Sagar Agarwal, Saket Agarwal, Krishna C. Aluri, Michael Arciprete, Christopher Brown, Klaus Charisse, Joseph Cichocki, Kevin Fitzgerald, Varun Goel, Yongli Gu, Dale Guenther, Bahru Habtemariam, Vasant Jadhav, Maja Janas, Muthusamy Jayaraman, Jeff Kurz, Jing Li, Steven Liou, Ju Liu, Xiumin Liu, Christopher Maclauchlin, Martin Maier, Muthiah Manoharan, Robin McDougall, Jay Nair, Diane Ramsden, Gabriel Robbie, Karyn Schmidt, Peter Smith, Christopher Theile, Akshay Vaishnaw, Scott Waldron, Jing-Tao Wu, Yuanxin Xu, Xuemei Zhang, Ivan Zlatev and Elena castellanos-Rizaldos
Drug Metabolism and Disposition June 21, 2021, DMD-MR-2021-000428; DOI: https://doi.org/10.1124/dmd.121.000428
Saeho Chong
1Drug Metabolism and Pharmacokinetics, Alnylam Pharmaceuticals Inc., United States
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Sagar Agarwal
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Saket Agarwal
3Investigative Toxicology, Alnylam Pharmaceuticals, United States
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Krishna C. Aluri
4Early Development, Alnylam pharmaceuticals, United States
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Michael Arciprete
5Alnylam Pharmaceuticals Inc., United States
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Christopher Brown
6Biology, Alnylam Pharmaceuticals, United States
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Klaus Charisse
7Chemistry, Alnylam Pharmaceuticals, United States
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Joseph Cichocki
8Toxicology, Vertex Pharmaceuticals, United States
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Kevin Fitzgerald
9Research, Alnylam Pharmaceuticals, United States
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Varun Goel
10Clinical Pharmacology, Avidity Bioscience, United States
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Yongli Gu
11Bioanalytical Science, Alnylam Pharmaceuticals, United States
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Dale Guenther
12RNAi Discovery, Alnylam Pharmaceuticals, United States
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Bahru Habtemariam
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Vasant Jadhav
6Biology, Alnylam Pharmaceuticals, United States
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Maja Janas
3Investigative Toxicology, Alnylam Pharmaceuticals, United States
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Muthusamy Jayaraman
13CRISPR Therapeutics, United States
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Jeff Kurz
14DMPK, Alnylam Pharmaceuticals, United States
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Jing Li
5Alnylam Pharmaceuticals Inc., United States
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  • ORCID record for Jing Li
Steven Liou
14DMPK, Alnylam Pharmaceuticals, United States
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Ju Liu
5Alnylam Pharmaceuticals Inc., United States
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Xiumin Liu
14DMPK, Alnylam Pharmaceuticals, United States
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Christopher Maclauchlin
14DMPK, Alnylam Pharmaceuticals, United States
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Martin Maier
14DMPK, Alnylam Pharmaceuticals, United States
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Muthiah Manoharan
9Research, Alnylam Pharmaceuticals, United States
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Robin McDougall
1Drug Metabolism and Pharmacokinetics, Alnylam Pharmaceuticals Inc., United States
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Jay Nair
7Chemistry, Alnylam Pharmaceuticals, United States
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Diane Ramsden
15DMPK, Takeda, United States
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Gabriel Robbie
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Karyn Schmidt
6Biology, Alnylam Pharmaceuticals, United States
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Peter Smith
5Alnylam Pharmaceuticals Inc., United States
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Christopher Theile
7Chemistry, Alnylam Pharmaceuticals, United States
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Akshay Vaishnaw
9Research, Alnylam Pharmaceuticals, United States
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Scott Waldron
9Research, Alnylam Pharmaceuticals, United States
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Jing-Tao Wu
16DMPK, Alnylam, United States
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  • For correspondence: jtwu@alnylam.com
Yuanxin Xu
5Alnylam Pharmaceuticals Inc., United States
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Xuemei Zhang
5Alnylam Pharmaceuticals Inc., United States
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Ivan Zlatev
7Chemistry, Alnylam Pharmaceuticals, United States
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Elena castellanos-Rizaldos
6Biology, Alnylam Pharmaceuticals, United States
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Data Supplement

  • Supplemental Data -

    Methods

    Supplemental Table 1 - In vitro evaluation of single and duplex stability in the presence of enzymes known to cleave RNA and DNA.

    Supplemental Table 2 - Cross species metabolite profiles from plated hepatocytes and nonclinical liver samples.

    Supplemental Figure 1 - Electrophoretic mobility shift assay (EMSA) results for siRNA2 and siRNA19 following a 1:1 mixture of sense strands (SS), antisense strands (AS) and duplex strands in PBS (Panel A).

    Supplemental Figure 2 - Evaluation of sense strand metabolites in rat (Panel A) and monkey (Panel B) liver samples following SC administration of siRNA6.

  View article

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