METHODS FOR INCREASING EFFICACY OF LIPID FORMULATED siRNA

Abstract

This invention relates to methods for increasing the efficiency of siRNA administrations via pre-administration of an agent that lowers LDL receptor levels.

1 . 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. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the agent is a statin or estradiol. 
     
     
         4 . The method of  claim 1 , wherein the agent is an inhibitor of PCSK9 expression. 
     
     
         5 . The method of  claim 1 , wherein the agent is a PCSK9 targeted siRNA. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 5 , wherein the PCSK9 targeted siRNA agent is administered at a dose of about 3 mg/kg. 
     
     
         9 . The method of  claim 1 , wherein the agent increases LDLR levels by at least 15%. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the gene targeted by the siRNA is expressed in hepatocytes or skin cells or adrenal gland cells or muscle cells or kidney cells. 
     
     
         15 . The method of  claim 1 , wherein the siRNA targets a VEGF, Eg5/KSP, TTR, GNAQ, HTT, PCSK9, SCAP, S14, MIG12, APOC3, APOB, PNPLA3, Hepcidin, or PCSK5 gene. 
     
     
         16 . The method of  claim 1 , wherein the siRNA targets a PCSK9 or VEGF and Eg5/KSP or TTR gene. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the subject is a human in need of treatment for a disease correlated with expression of the targeted gene. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein the first effective dose of the neutral liposomal formulated siRNA is at least 2 fold lower than the dose administered without the agent. 
     
     
         25 . The method of  claim 1 , wherein the first effective dose of the neutral liposomal formulated, siRNA is at least 10 fold lower than the dose administered without the agent. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the siRNA targets a PCSK9 gene and the first effective dose results in maintenance of at least a 40% decrease in total cholesterol levels. 
     
     
         28 . A method for administering a neutral liposomal formulated, PCSK9 targeted dsRNA to a human comprising administering to the human an initial dose of neutral liposomal formulated, PCSK9 targeted dsRNA resulting in an initial lowering of total serum cholesterol levels in the human by at least 15%, and subsequently administering a first effective dose of the neutral liposomal formulated, PCSK9 targeted dsRNA resulting in maintenance of lowering of total serum cholesterol levels in the human by at least 15%, wherein said first effective dose is at least two fold lower than a dose of the neutral liposomal formulated, PCSK9 targeted dsRNA administered to the subject without the initial dose of the PCSK9 targeted dsRNA. 
     
     
         29 . A method for increasing the uptake efficiency of a neutral liposomal formulated AD-9680 dsRNA in a subject comprising administering an initial bolus dose of 3 mg/kg of the neutral liposomal formulated AD-9680 to the subject resulting in a first result of a lowering in total serum cholesterol levels by about 60% 3 days after the initial dose, wherein after administering the initial dose, subsequent administrations of the neutral liposomal formulated AD-9680 at lower dosages of 1.0 or 0.3 mg/kg achieve a second result similar to the first result. 
     
     
         30 . A kit comprising an agent for lowering LDLR levels in a human and a lipid formulated gene siRNA targeting a gene. 
     
     
         31 . The kit of  claim 30 , wherein the agent is a statin or estradiol. 
     
     
         32 . The kit of  claim 30 , wherein the agent is an inhibitor of PCSK9 expression. 
     
     
         33 . The kit of  claim 30 , wherein the agent is a PCSK9 targeted siRNA. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . The kit of  claim 30 , wherein the siRNA targets a gene expressed in hepatocytes or skin cells or adrenal gland cells or muscle cells or kidney cells. 
     
     
         40 . The kit of  claim 30 , wherein the siRNA targets a VEGF, Eg5/KSP, HTT, GNAQ, TTR, PCSK-9, SCAP, S14, MIG12, APOC3, APOB, PNPLA3, Hepcidin, or PCSK5 gene. 
     
     
         41 . The kit of  claim 30 , wherein the siRNA targets a PCSK9 gene or a TTR gene, or a VEGF gene and an Eg5/KSP gene. 
     
     
         42 . The kit of  claim 30 , wherein the siRNA targets a PCSK9 gene. 
     
     
         43 . (canceled) 
     
     
         44 . (canceled)