title: Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: effect of dexamethasone co-treatment.
abstract: Despite recent progress, systemic delivery remains the major hurdle for development of safe and effective small inhibitory RNA (siRNA)-based therapeutics. Encapsulation of siRNA into liposomes is a promising option to overcome obstacles such as low stability in serum and inefficient internalization by target cells. However, a major liability of liposomes is the potential to induce an acute inflammatory response, thereby increasing the risk of numerous adverse effects. In this study, we characterized a liposomal siRNA delivery vehicle, LNP201, which is capable of silencing an mRNA target in mouse liver by over 80%. The biodistribution profile, efficacy after single and multiple doses, mechanism of action, and inflammatory toxicity are characterized for LNP201. Furthermore, we demonstrate that the glucocorticoid receptor (GR) agonist dexamethasone (Dex) inhibits LNP201-induced cytokine release, inflammatory gene induction, and mitogen-activated protein kinase (MAPK) phosphorylation in multiple tissues. These data present a possible clinical strategy for increasing the safety profile of siRNA-based drugs while maintaining the potency of gene silencing.
authors.affiliation: Department of RNA Therapeutics, Merck and Co., Inc, West Point, Pennsylvania 19486, USA. marc_abrams@merck.com
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.forename: Martin L
authors.initials: ML
authors.lastname: Koser
authors.forename: Jessica
authors.initials: J
authors.lastname: Seitzer
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Williams
authors.forename: Martha A
authors.initials: MA
authors.lastname: DiPietro
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Shaw
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Vasant
authors.initials: V
authors.lastname: Jadhav
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Paul A
authors.initials: PA
authors.lastname: Burke
authors.forename: Alan B
authors.initials: AB
authors.lastname: Sachs
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D020868:Gene Silencing; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists
chemical_list: D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone