Alnylam and Collaborators Discover Key Mechanism for Delivery of RNAi Therapeutics
News Jan 11, 2010
Alnylam Pharmaceuticals, Inc. announced that it has discovered a key mechanism related to the systemic delivery of RNAi therapeutics using lipid nanoparticles (LNPs).
The new pre-clinical research was presented at the "Advances in Biopharmaceuticals" Keystone Symposium held January 8-13, 2010 in Midway, Utah, and was performed in collaboration with scientists at the Max Planck Institute of Molecular Cell Biology and Genetics.
The data document a key mechanism for endogenous targeting of LNPs to the liver, provide alternative targeting strategies for the hepatic delivery of RNAi therapeutics, and highlight potential targeting approaches for delivery to non-hepatic tissues and cell types.
"A key achievement this past year was our progress in systemic delivery of RNAi therapeutics, the critical scientific determinant for advancement of this promising new class of medicines to patients," said Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished Alnylam Fellow.
"As noted recently, one dimension of our progress is evidenced by the discovery of novel LNP compositions that have markedly enhanced potency with efficacy achieved at microgram per kilogram dose levels. Today, we're very pleased to announce our discovery of a key mechanism for systemic delivery by LNPs, a finding that reveals a very promising new frontier for RNAi therapeutics with targeted delivery."
The new in vitro and in vivo research findings establish the role of ApoE as an endogenous targeting ligand for neutrally charged ionizable LNPs (iLNPs), but not certain cationic LNPs (cLNPs), and demonstrate an alternative targeting strategy for the hepatic delivery of RNAi therapeutics using the carbohydrate N-acetylgalactosamine (GalNAc) as an exogenous ligand.
Data from these studies showed:
- in cultured liver cells, ApoE enhanced both the cellular uptake and silencing activity of siRNAs formulated in iLNPs;
- in an ApoE knockout mouse model, iLNPs demonstrated a complete loss of activity due to the absence of ApoE as an endogenous targeting ligand;
- however, in vivo activity was found to be fully restored through the addition of an exogenous source of ApoE (recombinant ApoE, or "r-ApoE") when the protein was pre-mixed with iLNPs prior to their co-administration;
- specifically, the data showed that as little as 0.03 mg/kg of r-ApoE was able to fully restore the activity of an siRNA formulated in an iLNP; and,
- alternatively, in the same ApoE knockout model, silencing activity was found to be restored by the use of an exogenous GalNAc ligand that targets the iLNP to the asialoglycoprotein receptor (ASGR) expressed on hepatocytes, with as little as 0.15 mole% GalNAc ligand being sufficient to give near maximal activity.