Development of lipidoid-siRNA formulations for systemic delivery to the liver.
RNA interference therapeutics afford the potential to silence target gene expression specifically, thereby blocking production of disease-causing proteins. The development of safe and effective systemic small interfering RNA (siRNA) delivery systems is of central importance to the therapeutic application of siRNA. Lipid and lipid-like materials are currently the most well-studied siRNA delivery systems for liver delivery, having been utilized in several animal models, including nonhuman primates. Here, we describe the development of a multicomponent, systemic siRNA delivery system, based on the novel lipid-like material 98N(12)-5(1). We show that in vivo delivery efficacy is affected by many parameters, including the formulation composition, nature of particle PEGylation, degree of drug loading, and biophysical parameters such as particle size. In particular, small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids can result in significant effects on in vivo efficacy. The lead formulation developed is liver targeted (>90% injected dose distributes to liver) and can induce fully reversible, long-duration gene silencing without loss of activity following repeat administration.
Akinc
Akin
A
Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142, USA. dgander@mit.edu
Goldberg
Michael
M
Qin
June
J
Dorkin
J Robert
JR
Gamba-Vitalo
Christina
C
Maier
Martin
M
Jayaprakash
K Narayanannair
KN
Jayaraman
Muthusamy
M
Rajeev
Kallanthottathil G
KG
Manoharan
Muthiah
M
Koteliansky
Victor
V
Röhl
Ingo
I
Leshchiner
Elizaveta S
ES
Langer
Robert
R
Anderson
Daniel G
DG
D000818:Animals; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry; D005167:Factor VII / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry*
D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII