Method of delivering vectors to pancreas and lungs by cannulating the aorta
The present invention relates to a safe and effective way to deliver and express therapeutic compositions (e.g., transgenes) to the pancreas and lungs of a mammal.
1. A method of administering a therapeutic composition to a mammal in need thereof comprising:
(a) inserting a catheter into an umbilical or femoral artery in the mammal,
(b) advancing the catheter to the aorta (celiac or superior mesenteric artery), and
(c) delivering a therapeutic composition through the catheter to the celiac or superior mesenteric artery in the mammal,
wherein the therapeutic composition is an adeno-associated viral-9 (AAV9) vector encoding a nucleic acid encoding a therapeutic substance, and wherein the therapeutic substance is expressed in pancreatic duct epithelial cells or pancreatic polypeptide secreting cells of islets of the mammal, and wherein insulin, glucagon, somatostatin-secreting cells and acinar cells are not transduced in the mammal.
2. The method of claim 1 , further comprising:
(d) administering a saline flush after the administration of the therapeutic composition.
3. The method of claim 1 , wherein the viral vector is administered at a dose of at least 1.5×10 11 viral genomes.
4. The method of claim 1 , wherein the viral vector is administered at a dose of at least 2.5×10 12 viral genomes.
5. The method of claim 1 , wherein the viral vector is administered at a dose of at least 6.2×10 12 viral genomes.
6. The method of claim 1 , wherein the therapeutic substance is CFTR.
7. The method of claim 1 , wherein the therapeutic composition is expressed for more than 30 days in the mammal.
8. The method of claim 1 , wherein the therapeutic composition is expressed for more than 90 days in the mammal.
9. The method of claim 1 , wherein the therapeutic composition is expressed with a transduction efficiency of at least 15% in the lungs.
10. The method of claim 1 , wherein the therapeutic composition is expressed with a transduction efficiency of at least 20% in pancreas.
11. The method of claim 1 , wherein the therapeutic composition is expressed with a transduction efficiency of less than 1% in liver, stomach, spleen, heart, kidney, small intestine, colon, brain, thyroid, and/or vas deferens as compared to the pancreas or lung.
12. The method of claim 1 , wherein the therapeutic composition is expressed with a transduction efficiency of at least 1% in one or more of brain, salivary gland, trachea, heart, thymus, lung, diaphragm, liver, gallbladder wall, cystic duct, spleen, stomach, ileum, kidney, testicle, or vas deferens.
13. A method of treating pancreatic or lung disease in a mammal so as to treat the disease, the method comprising:
(a) inserting a catheter into an umbilical or femoral artery in the mammal to reach the aorta,
(b) advancing the catheter to the aorta (celiac or superior mesenteric artery), and
(c) delivering a therapeutic composition through the catheter to the celiac or superior mesenteric artery in the mammal,
wherein the therapeutic composition is an adeno-associated viral-9 (AAV9) viral particle comprising a vector comprising a nucleic acid encoding a therapeutic substance, and wherein the therapeutic substance is expressed in pancreatic duct epithelial cells or pancreatic polypeptide secreting cells of islets of the mammal, and wherein insulin, glucagon, somatostatin-secreting cells and acinar cells are not transduced in the mammal.
14. The method of claim 13 , wherein the method treats pancreatic disease in a mammal by transducing pancreatic epithelia in the mammal, and wherein the therapeutic composition is expressed in the pancreas of the mammal.
15. The method of claim 14 , wherein the method further transduces lung submucosal glands in the mammal.
16. The method of claim 15 , wherein the method treats lung disease in a mammal by transducing lung submucosal glands in the mammal, and wherein the therapeutic composition is expressed in the submucosal glands in the lung of the mammal.
17. The method of claim 1 , wherein the catheter is inserted into an umbilical artery.