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Others examples of said agents include but are not limited to berberine, HMG CoA Reductase inhibitors, Squalene Synthetase inhibitors, HMG CoA Synthetase inhibitors, fenofibrates, LDLR RNAa, IDOL targeted siRNA, niacin, and ezetimibe.

Examples of said agents include but are not limited to statins, estradiols, or an inhibitor of PCSK9 expression, e.g., a PCSK9 targeted siRNA.

The agent increases levels of LDL receptor by, e.g., at least 15%. In some embodiments the first effective dose is administered within 3 days of administering the agent. Also disclosed are kits comprising the lipid formulated siRNA and the LDLR increasing agent.ДЄccording, the invention provides a method for administering a neutral liposomal formulated, siRNA targeting a gene to a subject comprising administering to the subject an agent that increases LDLR levels, and subsequently administering a first effective dose of the neutral liposomal formulated, siRNA targeting a gene, wherein said first effective dose is lower than a dose of the neutral liposomal formulated siRNA administered to the subject without the agent. SUMMARY OF THE INVENTIONДisclosed herein are methods for increasing the efficacy of lipid formulated siRNAs via administration of an agent that increases LDL receptor (LDLR) levels. The dsRNA, e.g., siRNA, can be formulated in a number of formulations including, e.g., a lipid formulation. This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene. and WO 99/61631, Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al. WO 99/32619 (Fire et al.) discloses the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in C. Recently, double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). This invention relates to methods for increasing the efficacy of lipid formulated siRNA.

15, 2009, the entire disclosures of which are hereby incorporated by reference in their entirety for all purposes. 15, 2010, which claims the benefit of U.S. В§ 371 National Stage Application of International Patent Application No.

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