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Posted: May 11, 2010

Key Mechanism for Delivery of RNAi Therapeutics with Lipid Nanoparticles

(Nanowerk News) Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today the publication of pre-clinical research in the journal Molecular Therapy revealing key mechanisms related to the systemic delivery of RNAi therapeutics using lipid nanoparticles (LNPs). The new study (Akinc et al., Molecular Therapy, doi:10.1038/mt.2010.85, 2010), performed in collaboration with scientists at the Max Planck Institute of Molecular Cell Biology and Genetics and AlCana Technologies, Inc., describes a mechanism for endogenous apolipoprotein E (apoE)-mediated targeting of LNPs to the liver, demonstrates alternative ligand-directed targeting strategies for liver delivery of RNAi therapeutics, and highlights potential targeting approaches for delivery to tissues and cell types beyond the liver.
“In recent months, we have made tremendous progress in the delivery of RNAi therapeutics, a critical determinant for advancement of this promising new class of medicines to patients and for realizing the fullest potential of this technology,” said Akin Akinc, Ph.D., Associate Director, Research at Alnylam. “In particular, the findings published today reveal key mechanisms for the delivery of LNP-encapsulated siRNAs to the liver, and more generally, suggest strategies for achieving targeted delivery to tissues and cell types beyond the liver. These mechanistic findings, along with our recent work on the discovery of next-generation LNPs, demonstrate the considerable progress made both in our understanding and in our utilization of LNPs for the delivery of RNAi therapeutics.”
Preliminary results from this study were previously presented at the Advances in Biopharmaceuticals Keystone Symposium in January 2010, demonstrating that ApoE is an endogenous targeting ligand for neutrally charged ionizable LNPs (iLNPs), but not certain cationic LNPs (cLNPs). Further, iLNPs were engineered with the carbohydrate N-acetylgalactosamine (GalNAc) to achieve targeting to the asialoglycoprotein receptor (ASGPR) as an alternative targeting strategy for the hepatic delivery of RNAi therapeutics. Specifically, the in vitro and in vivo data showed that:
  • in cultured liver cells, ApoE was required for both the cellular uptake and silencing activity of siRNAs formulated in iLNPs, but not for siRNAs formulated in cLNPs;
  • in an ApoE knockout mouse model, iLNPs demonstrated a complete loss of gene silencing 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 to ApoE knock-out mice; specifically, as little as 0.03 mg/kg of r-ApoE was able to fully restore the activity of an siRNA formulated in an iLNP;
  • alternatively, in the same ApoE knockout model, silencing activity was found to be restored by the use of an exogenous GalNAc ligand to engineer iLNPs for targeting to the ASGPR expressed on hepatocytes, with as little as 0.15 mole% GalNAc ligand per LNP particle being sufficient to give near maximal in vivo activity.
  • Additional findings in today’s publication highlights that:
  • in a low density lipoprotein receptor (LDLR) knockout mouse model, in vivo silencing activity of iLNPs was greatly diminished due to the absence of LDLR as a key hepatic receptor for ApoE; and,
  • similarly, in an ASGPR knockout mouse model, in vivo silencing activity of GalNAc-targeted iLNPs was nearly abolished indicating that the GalNAc-ASGPR interaction is responsible for the in vivo activity of the GalNAc-targeted iLNP.
  • LNP formulations represent one of several approaches Alnylam is pursuing for systemic delivery of RNAi therapeutics. Additional approaches include novel lipidoid formulations, including cationic LNPs (cLNPs); mimetic lipoprotein particles (MLPs); siRNA conjugation strategies; and single-stranded RNAi; amongst others. Alnylam is currently enrolling patients in a Phase I clinical program with its systemic RNAi therapeutic ALN-VSP for the treatment of liver cancers. In addition, Alnylam intends to initiate a Phase I trial in the first half of 2010 for an additional systemic RNAi therapeutic, ALN-TTR01 for the treatment of transthyretin (TTR)-mediated amyloidosis. ALN-VSP and ALN-TTR01 both utilize a first generation LNP formulation known as stable nucleic acid-lipid particles (SNALP), which contains an ionizable lipid, and is developed in collaboration with Tekmira Pharmaceuticals Corporation. Alnylam is also advancing its second generation LNP platform in its ALN-TTR02 and ALN-PCS programs, currently in pre-clinical development.
    About RNA Interference (RNAi)
    RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
    About Alnylam Pharmaceuticals
    Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world’s top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics for the treatment of a wide range of disease areas, including respiratory syncytial virus (RSV), liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington’s disease. In addition, Alnylam formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in manufacturing processes for biotherapeutic products, including recombinant proteins and monoclonal antibodies. The company’s leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA-based therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit
    Source: Alnylam Pharmaceuticals (press release)
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