Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: effect of dexamethasone co-treatment.
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.
Abrams
Marc T
MT
Department of RNA Therapeutics, Merck and Co., Inc, West Point, Pennsylvania 19486, USA. marc_abrams@merck.com
Koser
Martin L
ML
Seitzer
Jessica
J
Williams
Stephanie C
SC
DiPietro
Martha A
MA
Wang
Weimin
W
Shaw
Andrew W
AW
Mao
Xianzhi
X
Jadhav
Vasant
V
Davide
Joseph P
JP
Burke
Paul A
PA
Sachs
Alan B
AB
Stirdivant
Steven M
SM
Sepp-Lorenzino
Laura
L
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
D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone