Multiple site delivery of adenoviral vector for the induction of angiogenesis

Abstract

The present invention provides a method for enhancing the level of perfusion of blood to a target tissue, treating a target tissue suffering from or at risk of suffering from ischemic damage, inducing angiogenesis in a target tissue, and/or inducing collateral blood vessel formation in a target tissue affected by or at risk of being affected by a vascular occlusion. The present inventive method comprises administering to the target tissue a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that the level of perfusion of blood to the target tissue is enhanced, the dose has a therapeutic or prophylactic effect on the target tissue, angiogenesis is induced in the target tissue, and/or the adenoviral vector contacts a region including the source, the terminus, and an area therebetween for the collateral blood vessel formation, and collateral blood vessel formation is induced.

What is claimed is:  
     
         1 . A method of inducing collateral blood vessel formation in a heart, wherein the method comprises directly injecting to the heart, via multiple injections to different points on the internal surface of the heart, a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that collateral blood vessels are formed within the heart.  
     
     
         2 . The method of  claim 1 , wherein the heart is affected by a vascular occlusion.  
     
     
         3 . The method of  claim 1 , wherein the heart is suffering from or at risk of suffering from ischemia.  
     
     
         4 . The method of  claim 1 , wherein the multiple injections are administered to about 0.5-15 cm 3  of the target tissue.  
     
     
         5 . The method of  claim 4 , wherein at least 2 of the multiple injections are administered within about 10 minutes.  
     
     
         6 . The method of  claim 5 , wherein all of the multiple injections are administered within about 10 minutes.  
     
     
         7 . The method of  claim 6 , wherein the multiple injections are substantially simultaneous.  
     
     
         8 . The method of  claim 1 , wherein at least 2 of the multiple injections are administered within about 10 minutes.  
     
     
         9 . The method of  claim 8 , wherein all of the multiple injections are administered within about 10 minutes.  
     
     
         10 . The method of  claim 1 , wherein the angiogenic peptide is selected from the group consisting of VEGF 121 , VEGF 145 , VEGF 165 , and VEGF 189 .  
     
     
         11 . The method of  claim 1 , wherein the angiogenic peptide is selected from the group consisting of VEGF II, VEGF-C, FGF-4, angiogenin, angiogenin-2, and P1GF.  
     
     
         12 . The method of  claim 1 , wherein the adenoviral vector is deficient in at least one essential gene function of the E1 region of the adenoviral genome.  
     
     
         13 . The method of  claim 1 , wherein the adenoviral vector is deficient in part of the E3 region.  
     
     
         14 . The method of  claim 1 , wherein the adenoviral vector has at least a partial deletion of the E1a region, at least a partial deletion of the E1b region, and at least a partial deletion of the E3 region.  
     
     
         15 . The method of  claim 1 , wherein the adenoviral vector is deficient in at least one essential gene function of the E4 region of the adenoviral genome.  
     
     
         16 . The method of  claim 1 , wherein the adenoviral vector has at least a partial deletion of the E1 region, at least a partial deletion of the E3 region, and at least a partial deletion of the E4 region.  
     
     
         17 . The method of  claim 1 , wherein the DNA is inserted into a region of the adenoviral vector such that, when transcribed, the direction of transcription of the DNA is opposite the direction of transcription of the region into which the DNA is inserted.  
     
     
         18 . The method of  claim 1 , wherein the DNA is positioned in the E1 region of the adenoviral genome.  
     
     
         19 . The method of  claim 1 , wherein the multiple injections comprise at least 4 injections.  
     
     
         20 . The method of  claim 19 , wherein the multiple injections comprise at least 8 injections.  
     
     
         21 . The method of  claim 20 , wherein the multiple injections comprise at least 15 injections.  
     
     
         22 . The method of  claim 1 , wherein the DNA encodes multiple peptides.  
     
     
         23 . The method of  claim 22 , wherein the DNA encodes an angiogenic peptide and an angiogenic peptide receptor.  
     
     
         24 . A method of bypassing a vascular occlusion in a tissue, wherein the method comprises administering to the tissue a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) a DNA encoding an angiogenic peptide, wherein the dose of the pharmaceutical composition is administered via multiple applications to the tissue to at least a first location, a second location, and an area therebetween, such that collateral blood vessels are formed between the first location and second location within the tissue, thereby allowing blood flow in the tissue to bypass the vascular occlusion.  
     
     
         25 . The method of  claim 24 , wherein the DNA is present in an adenoviral vector.  
     
     
         26 . The method of  claim 25 , wherein the tissue is affected by a vascular occlusion.  
     
     
         27 . The method of  claim 25 , wherein the tissue is suffering from or at risk of suffering from ischemia.  
     
     
         28 . The method of  claim 25 , wherein the multiple applications are administered to about 0.5-15 cm 3  of the tissue.  
     
     
         29 . The method of  claim 26 , wherein at least 2 of the multiple applications are administered within about 10 minutes.  
     
     
         30 . The method of  claim 29 , wherein all of the multiple applications are administered within about 10 minutes.  
     
     
         31 . The method of  claim 30 , wherein the multiple applications are substantially simultaneous.  
     
     
         32 . The method of  claim 25 , wherein at least 2 of the multiple applications are administered within about 10 minutes.  
     
     
         33 . The method of  claim 32 , wherein all of the multiple applications are administered within about 10 minutes.  
     
     
         34 . The method of  claim 25 , wherein the angiogenic peptide is selected from the group consisting of VEGF 121 , VEGF 145 , VEGF 165 , and VEGF 189 .  
     
     
         35 . The method of  claim 25 , wherein the angiogenic peptide is selected from the group consisting of VEGF II, VEGF-C, FGF-4, angiogenin, angiogenin-2, and P1GF.  
     
     
         36 . The method of  claim 25 , wherein the adenoviral vector is deficient in at least one essential gene function of the E1 region of the adenoviral genome.  
     
     
         37 . The method of  claim 25 , wherein the adenoviral vector is deficient in part of the E3 region.  
     
     
         38 . The method of  claim 25 , wherein the adenoviral vector has at least a partial deletion of the E1a region, at least a partial deletion of the E1b region, and at least a partial deletion of the E3 region.  
     
     
         39 . The method of  claim 25 , wherein the adenoviral vector is deficient in at least one essential gene function of the E4 region of the adenoviral genome.  
     
     
         40 . The method of  claim 25 , wherein the adenoviral vector has at least a partial deletion of the E1 region, at least a partial deletion of the E3 region, and at least a partial deletion of the E4 region.  
     
     
         41 . The method of  claim 25 , wherein the DNA is inserted into a region of the adenoviral vector such that, when transcribed, the direction of transcription of the DNA is opposite the direction of transcription of the region into which the DNA is inserted.  
     
     
         42 . The method of  claim 25 , wherein the DNA is positioned in the E1 region of the adenoviral genome.  
     
     
         43 . The method of  claim 25 , wherein the dose of the pharmaceutical composition is administered via multiple injections to the tissue.  
     
     
         44 . The method of  claim 43 , wherein the multiple injections comprise at least  4  injections.  
     
     
         45 . The method of  claim 44 , wherein the multiple injections comprise at least 8 injections.  
     
     
         46 . The method of  claim 45 , wherein the multiple injections comprise at least 15 injections.  
     
     
         47 . The method of  claim 25 , wherein the dose is administered ex vivo to the tissue.  
     
     
         48 . The method of  claim 25 , wherein the dose is administered in vivo to the tissue.  
     
     
         49 . The method of  claim 25 , wherein the DNA encodes multiple peptides.  
     
     
         50 . The method of  claim 49 , wherein the DNA encodes an angiogenic peptide and an angiogenic peptide receptor.