Intravenous delivery of polynucleotides to cells in mammalian limb

• US 20040242528A1
• Filed: 05/27/2004
• Published: 12/02/2004
• Est. Priority Date: 05/28/2003
• Status: Active Grant

• Current Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Roche Madison Inc. (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Hagstrom, James E., Hegge, Julia
• Granted Patent: US 7,803,782 B2
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

An intravenous delivery method is described that enables delivery of polynucleotides to extravascular cells of a mammalian limb. The method involves the injection of polynucleotides into a distal vein of a limb that is transiently occluded. Polynucleotide delivery is facilitated by rapid injection in sufficient volume to enable extravasation of the solution into surrounding tissue.

Claims

1. A process for delivering a polynucleotide to an extravascular cell in a limb of a mammal comprising:

a) inserting an injection devise into a vein in said limb;

b) forming an occlusion of said vein proximal to an intended site of injection of said polynucleotide; and

,

c) injecting said polynucleotide in a solution into said vein thereby delivering said polynucleotide to said extravascular cell in said limb distal to said occlusion.

2. The process of claim 1 wherein said vein consists of a superficial vein.

3. The process of claim 1 wherein said vein consists of a deep vein.

4. The process of claim 1 wherein said polynucleotide is injected into said vein in an antegrade direction.

5. The process of claim 1 wherein forming an occlusion comprises applying a device for impeding blood flow to the surface of the skin of said limb and applying sufficient pressure against said limb with said device to impede blood flow to and from said limb.

6. The process of claim 5 wherein said device for impeding blood flow is selected from the group consisting of:

tourniquet, double tourniquet, double cuff tourniquet, cuff, sphygmomanometer, oscillotonometer, oscillometer, and haemotonometer.

7. The process of claim 1 wherein said injector is selected from the group consisting of:

catheter, syringe needle, cannula, stylet, balloon catheter, multiple balloon catheter, single lumen catheter, and multilumen catheter.

8. The process of claim 1 wherein said extravascular cell is selected from the group consisting of:

skeletal muscle cell, myofiber, myocyte, joint cell, synovial cell, cartilage cell, connective tissue cell, fibroblast, fibrocyte, chondrocyte, mesenchyme cell, mast cells, macrophages, histiocyte, tendon cell, capsular cells, bone cell, osteocyte, osteoclast, osteoblast, bone marrow cell, hematopoietic cell, skin cell, lymph node cell and stroma cell.

9. The process of claim 1 wherein said polynucleotide consists of a naked polynucleotide.

10. The process of claim 1 wherein said polynucleotide consists of a virally associated polynucleotide.

11. The process of claim 10 wherein the virus consists of an adenoassociated virus.

12. The process of claim 10 wherein the virus consists of an adenovirus.

13. The process of claim 1 wherein said polynucleotide is associated with a transfection agent.

14. The process of claim 1 wherein said polynucleotide consists of an expressible gene.

15. The process of claim 14 where said gene encodes a polypeptide selected from the list consisting of:

secreted protein, endocrine factor, non-secreted protein, antigen, and therapeutic polypeptide.

16. The process of claim 1 wherein said polynucleotide alters the expression of a gene in said cell.

17. The process of claim 1 wherein said polynucleotide is selected from the group consisting of:

siRNA, antisense polynucleotide, ribozyme, RNAi inducing polynucleotide, and gene encoding an siRNA or antisense polynucleotide.

18. The process of claim 16 wherein said polynucleotide alters mRNA splicing.

19. The process of claim 16 wherein said polynucleotide alters mRNA levels.

20. The process of claim 1 further comprising injecting into a vessel in said limb one or more compounds to increase vessel permeability.

21. The process of claim 1 further comprising administering to said mammal one or more compounds selected from the list consisting of anesthetic and analgesic.

22. The process of claim 1 wherein said mammal has a disease.

23. The process of claim 22 wherein said disease is selected from the list consisting of:

metabolic disease, muscular disease, muscle injury, muscle atrophy, cancer, infectious disease, vascular disease, circulatory disorder, endocrine disorder, immune disorder.

24. The process of claim 1 wherein said mammal is at risk of having a disease.

25. The process of claim 1 wherein said solution consists of a volume that is greater than about 0.2 ml per ml of target limb displacement volume.

26. A process for delivering a molecule to an extravascular cell in a limb of a mammalian comprising;

a) inserting an injection device into a vein in said limb;

b) forming an occlusion of said vein proximal to an intended site of injection of said polynucleotide; and

,

c) injecting said molecule in a solution into said vein thereby delivering said polynucleotide to said extravascular cell in said limb distal to said occlusion.

27. The process of claim 26 wherein said molecule consists of a biologically active compound.

28. A process for delivering a siRNA polynucleotide or siRNA-expressing polynucleotide to an extravascular cell in a primate comprising:

a) inserting an injection device into a vein; and

,

b) injecting said molecule in a solution into said vein thereby delivering said polynucleotide to said extravascular cell.