title: Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates.
abstract: The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: stephanie_barrett@merck.com.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Barrett
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rob S
authors.initials: RS
authors.lastname: Burke
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Bason
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Busuek
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Carlini
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Carr
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Crocker
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Guidry
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Jun H
authors.initials: JH
authors.lastname: Heo
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Howell
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kemp
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kowtoniuk
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Latham
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Leone
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lyman
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rubina G
authors.initials: RG
authors.lastname: Parmar
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mihir
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sergey Y
authors.initials: SY
authors.lastname: Pechenov
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Pei
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Conrad
authors.initials: C
authors.lastname: Raab
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Riley
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sheri
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Soli
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Staskiewicz
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Stern
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Vavrek
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Waldman
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Young
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: D000818:Animals; D001345:Autoradiography; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D008253:Macaca mulatta; D009757:Nylons / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000633:toxicity; D011877:Radionuclide Imaging; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D009757:Nylons; D010455:Peptides; D034741:RNA, Small Interfering
keywords: Biodegradable; Delivery vehicle; Gene delivery; Polypeptide