Method for enhanced uptake of viral vectors in the myocardium
The present invention relates to improved therapies for the treatment of heart disease, particularly the improved delivery of therapeutic agents to heart tissue by direct infusion into the coronary circulation. A preferred embodiment of the invention is a method comprising, identifying a mammal in need of treatment or prevention of heart disease, and supplying NO to the coronary circulation prior to, and/or during the infusion of a therapeutic polynucleotide into a blood vessel of the coronary circulation in vivo.
1. A method of treating heart failure by transfecting cardiac cells of a human, the method comprising:
identifying a human in need of treatment for heart failure;
intravenously administering nitroglycerin to said human at an initial does of 10-20 μg/minute at least 25 minutes prior to administration of a therapeutic polynucleotide and continuing to intravenously administer nitroglycerin during administration of said therapeutic polynucleotide; and
administering a therapeutic polynucleotide into a lumen of a coronary artery in vivo for at least about 10 minutes, wherein said coronary artery comprises the left coronary artery, the right coronary artery, or the left and right coronary artery;
wherein a coronary circulation is not isolated or substantially isolated from a systemic circulation of the human, wherein said therapeutic polynucleotide comprises a SERCA2a coding sequence, said therapeutic polynucleotide is packaged in a DNAse resistant particle (DRP) of a AAV2/1 viral vector, and a total number of DRP infused into said lumen is not more than about 1×10 14 , and wherein said therapeutic polynucleotide transfects cardiac cells of said human resulting in the treatment of said heart failure.
2. The method of claim 1 , wherein said treatment improves a measurement of absolute ejection fraction of said human's heart six months after said treatment as compared to a measurement of absolute ejection fraction of said human's heart prior to said treatment.
3. The method of claim 1 , wherein a total of at least 500 μg nitroglycerin prior to administration of said therapeutic polynucleotide.
4. The method of claim 1 , wherein said human does not have neutralizing anti-AAV1 antibodies at titer ≧1:4.
5. The method of claim 1 , wherein the therapeutic polynucleotide is infused at a flow rate of 4 to 6 ml/min.
6. The method of claim 1 , wherein the therapeutic polynucleotide is administered in a volume of 50 ml to 70 ml.
7. The method of claim 1 , wherein about ⅔ of the therapeutic polynucleotide is administered to the left coronary artery and the remainder is administered to the right coronary artery.
8. The method of claim 1 , wherein the total number of DRP infused into said lumen is from about 1×10 12 to about 1×10 13 .
9. The method of claim 1 , wherein no other vasodilator or vascular permeation enhancer is administered to said mammal.
10. The method of claim 9 , wherein a total of at least 500 μg nitroglycerin prior to administration of said therapeutic polynucleotide, wherein said human does not have neutralizing anti-AAV1 antibodies at titer ≧1:4, wherein the therapeutic polynucleotide is administered in a volume of 50 ml to 70 ml at a flow rate of 4 to 6 ml/min, wherein about ⅔ of the therapeutic polynucleotide is administered to the left coronary artery and the remainder is administered to the right coronary artery, and wherein the total number of DRP infused into said lumen is from about 1×10 12 to about 1×10 13 .
11. The method of claim 10 , wherein said treatment improves a measurement of absolute ejection fraction of said human's heart six months after said treatment as compared to a measurement of absolute ejection fraction of said human's heart prior to said treatment.
12. The method of claim 10 , wherein the therapeutic polynucleotide is administered in a volume of 60 ml at a flow rate of 5 ml/min, and wherein the total number of DRP infused into said lumen is about 1×10 13 .