Compositions for targeted delivery of siRNA

• US 10,316,316 B2
• Filed: 04/19/2016
• Issued: 06/11/2019
• Est. Priority Date: 02/24/2010
• Status: Active Grant

• Current Assignee: Arrowhead Pharmaceuticals, Inc.
• Original Assignee: Arrowhead Pharmaceuticals, Inc.
• Inventors: Lewis, David L, Rozema, David B, Wakefield, Darren H, Hoffman, Torsten, Kitas, Erik, Mohr, Peter, Hadwiger, Philipp, Thuer, Wilma, Valis, Linda
• Primary Examiner(s): Angell, J. E.
• Application Number:
  US15/132,695
• Publication Number:
  US 20160222384A1
• Time in Patent Office: 1,148 Days
• Field of Search: None
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.

Claims

1. A composition for delivering an RNA interference polynucleotide to a cell in vivo comprising:

N-A and

2. The composition of claim 1 wherein the RNA interference polynucleotide is selected from the group consisting of:

DNA, RNA, dsRNA, siRNA, and miRNA.

3. The composition of claim 1 wherein the value y+z is greater than 70% of the number of amines on the membrane active polyamine.

4. The composition of claim 1 wherein the value y+z is greater than 80% of the number of amines on the membrane active polyamine.

5. The composition of claim 1 wherein the value y+z is greater than 90% of the number of amines on the membrane active polyamine.

6. The composition of claim 1 wherein the composition is provided in a pharmaceutically acceptable carrier or diluent.

7. The composition of claim 1 wherein the galactose derivative consists of an N-acetylgalactosamine.

8. The composition of claim 1 wherein the steric stabilizer consists of an polyethylene glycol.

9. The composition of claim 1 wherein the hydrophobic group comprises cholesterol.

10. The composition of claim 1 wherein the hydrophobic group comprises a cholesterol derivative.

11. A composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:

12. The composition of claim 11 wherein the RNA interference polynucleotide is selected from the group consisting of:

DNA, RNA, dsRNA, siRNA, and miRNA.

13. The composition of claim 12 wherein the value y+z is greater than 70% of the number of amines on the membrane active polyamine.