SYSTEMS AND METHODS FOR LEFT VENTRICULAR UNLOADING IN BIOLOGIC THERAPY OR VECTORED GENE THERAPY

Abstract

Methods and systems for using mechanical circulatory support concurrently with a biologic therapy (e.g. a gene therapy vector). Particular adaptations include a cardiac therapy method in which a blood vessel such as a coronary artery or blood vessel is occluded, followed by injecting a gene therapy vector or biologic distal to the occlusion site and waiting a certain amount of time, while using the mechanical circulatory support system to provide circulatory support to the patient.

Description

BACKGROUND

Cardiovascular diseases are a leading cause of morbidity, mortality, and burden on healthcare around the world. A variety of treatment modalities have been developed for cardiovascular disease, ranging from pharmaceuticals to mechanical devices and finally transplantation. Temporary cardiac support devices, such as ventricular assist devices, provide hemodynamic support, and facilitate heart recovery. Some ventricular assist devices are percutaneously inserted into the heart and can run in parallel with the native heart to supplement cardiac output, such as the IMPELLA® family of devices (Abiomed, Inc., Danvers Mass.).

Genetic manipulation through the transfer of genes to a target can be used to treat cells or organs, such as the heart. See e.g. Julie A. Wolfram, PhD et al., Gene Therapy to Treat Cardiovascular Disease, JAHA Vol 2, Issue 4 (2013) (“Wolfram”), incorporated herein by reference in its entirety. Gene therapy methods include the use of one or more gene therapy vectors, either viral or non-viral. For viral vectors, the genome of a virus can be programmed, and the virus injected into a patient as a gene therapy vector, with the expectation that the virus genome will express in the patient. At least one example of viral vectors includes adeno-associated viruses (AAVs). Administration of the vector can be done through injections or perfusions in different locations. For example, coronary perfusion can be used to deliver a vector genome globally across the myocardium. High gene expression is generally needed to achieve a therapeutic effect. At least one disadvantage of administering the viral vector in a coronary is the relative inefficiency of the technique, as the vector genome is rapidly delivered into system circulation by the heart. Due to the heart pumping, the clearance rate of the vector genome through the heart can be too high to achieve the desired gene expression. The virus passes through the heart relatively quickly, with relatively little time to adhere to the myocardium and transduce enough of the myocardium. The same issues arise with administration of biologic therapies to the heart. Techniques which arrest the heart to reduce the clearance rate of the vector genome or biologic and increase retention in the heart result in cardiac instability and/or ischemia.

It is therefore desirable to have systems and methods which can reduce the clearance rate of a vector genome or biologic in the heart without the downsides associated with stopping or slowing the heart.

BRIEF SUMMARY

The methods, systems, and devices described herein enable efficient delivery of biologic therapy, such as, but not limited to, a gene therapy vector to the myocardium by (i) temporarily blocking blood flow to the myocardium to increase the uptake of the biologic therapy (e.g. a gene therapy vector) in the myocardium and reduce clearance of the biologic therapy (e.g. the gene therapy vector) through the heart, (ii) while operating a mechanical circulatory support device in the heart concurrently with the injection of the biologic therapy (e.g. vector gene therapy) to maintain heart function and systemic circulation without adverse effects for the patient. At least one advantage of these methods, systems and devices is the ability to increase deposition of the biologic therapy (e.g. the gene therapy vector) within the myocardium. By deploying an angioplasty balloon in at least one coronary (i.e. the arteries and vessels with surround and supply the heart) to temporarily stop blood flow, and injecting a biologic therapy such as a gene therapy vector virus distal of the deployed balloon, the virus medium is pooled in the coronary artery, providing the therapy such as the virus vector with significantly more time to transduce the heart muscle. Operating a mechanical circulatory support device while injecting the biologic therapy maintains the cardiac output necessary for life and bridges the patient through potential ischemic events caused by the inflated angioplasty balloon—the mechanical circulatory support device acting as a temporary heart bypass. The mechanical support device can be a blood pump, such as an Impella device. In some embodiments, biologic therapy such as a gene therapy vector can be targeted to particular heart tissues, such as fibroblasts or endothelial cells. In some embodiments, one or more gene therapy vectors can be employed to preferentially target myocytes, fibroblasts, endothelial cells or other target tissues.

In a first illustrative embodiment, a method of treating a heart comprises operating a mechanical circulatory support device to support the heart. In some embodiments, the mechanical circulatory support device is operated outside the patient and in other embodiments the mechanical circulatory support device is inserted into the patient. The method further comprises operating the mechanical circulatory support device for a support period, and administering a biologic therapy such as a gene therapy vector to the heart during the support period. In an example, the gene therapy vector is administered within a blood vessel in the heart. In another example, the method further comprises inserting an angioplasty balloon in the blood vessel and inflating the balloon to temporarily occlude the blood vessel. In one example, the gene therapy vector is administered to the heart at a location distal of the angioplasty balloon. For example, the gene therapy vector is administered within the coronary artery downstream from the inflated balloon. In some examples, the gene therapy vector can be administered over the course of several periods. For example, a first dose of gene therapy vector is administered to the heart during a first administration period, followed by a second dose of gene therapy vector to the heart during a second administration period, with both administration periods separated by a rest period. In one example the rest period is longer than the first administration period. In one example, the inflated angioplasty balloon temporarily occludes the vessel for less than about three minutes, preferably one minute. In one example, the support period during which the mechanical circulatory support device, e.g. a microaxial transvalvular pump, is used is longer than 10 minutes. The support device is operated during the different administration periods and the rest period. In an example, administering the gene therapy vector to the heart is configured to increase an expression of vector DNA in cardiac tissue. The gene therapy vector may be targeted to tissues within the heart including the myocardium, fibroblasts, endothelial cells, or other cardiac tissue.

In a second illustrative embodiment, a method of supporting a patient's heart, comprises percutaneously inserting a blood pump into the heart and positioning the blood pump across the aortic valve of the heart. The method further comprises operating the blood pump to unload the left ventricle of the heart, and concurrently operating the blood pump and injecting a gene therapy vector into a coronary of the heart that is occluded in the manner described herein.

In a third illustrative embodiment, a method of upregulating gene expression in a patient's myocardium comprises placing a balloon in a coronary artery of a patient, and inflating the balloon for a first period to temporarily block blood flow within the coronary artery during the first period. The method further comprises placing a blood pump into a heart of the patient and positioning the pump across an aortic valve of the heart before operating the blood pump in the heart of the patient during a second period. The method comprises injecting a gene therapy vector within the coronary artery at a location distal of the inflated balloon during the first period, and deflating the balloon after the first period to restore blood flow within the coronary artery. In this illustrative embodiment, the first period occurs during the second period and the first period has a duration that does not cause permanent ischemia in cells of the myocardium. In one example, the method includes injecting the biologic therapy such as the gene therapy vector within the coronary artery at the location distal of the inflated balloon during the second period. In another example, the method includes injecting the gene therapy vector within the coronary artery at the location distal of the inflated balloon during a third period less than or equal to the second period. The duration of the first period may be less than three minutes, preferably less than one minute.

In a fourth illustrative embodiment, a method of supporting a patient's heart comprises administering biologic therapy such as a gene therapy vector within the heart. The method further comprises reducing the rate of clearance of the biologic therapy such as the gene therapy vector through the heart. In those embodiments where the biologic therapy is a gene therapy vector, the reduced rate of clearance causes expression of the gene therapy vector in the heart, causing transduction of the heart by the gene therapy vector, or any combination of these. In one example, the method deploys a mechanical circulatory support device and a balloon catheter to the heart.

In a fifth illustrative embodiment, a cardioprotective system for supporting a patient's heart that has undergone cardiogenic shock or myocardial infarction deploys a mechanical circulatory support device configured to be inserted and operated in the patient and a balloon catheter having an inflatable balloon with a proximal end and a distal end. The balloon catheter comprises an inflation catheter in fluid connection with the proximal end of the balloon, and the balloon configured to be inserted in a coronary artery of the patient for concurrent use with the mechanical circulatory support device. The system further deploys a delivery catheter for delivering a gene vector therapy in vivo, the delivery catheter having a proximal end with an inlet opening configured to receive a solution containing the gene therapy vector, a distal end with an outlet opening, and a tube extending between the proximal and distal ends of the delivery catheter. The balloon is configured to occlude blood flow at least partially through the coronary artery when inflated. In one example, the mechanical circulatory support device is a catheter-based intravascular blood pump. In another example, the outlet opening is configured to be positioned distal of the distal end of the balloon when the balloon is inflated. In yet another example, the tube extending between the proximal and distal ends of the delivery catheter has a longitudinal length that is longer than the balloon. In another example, the balloon catheter is configured such that upon balloon inflation, the balloon catheter outlet opening is not impeded by the balloon. In those embodiments where the gene therapy vector is administered, the vector may include non-native nucleic acid material that codes for a peptide that has a cardioprotective function when expressed in vivo, the gene therapy vector being configured to be absorbed by myocardial cells.

In a sixth illustrative embodiment, a method of treating a heart includes operating a mechanical circulatory support device to support the heart. The method further includes operating the mechanical circulatory support device for a support period, occluding at least one heart vessel and administering a biologic therapy to the occluded heart vessel. Biologic therapies can be adapted to preferentially target myocytes, fibroblasts, endothelial cells or other target tissues.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing and other objects and advantages will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which:

FIG. 1 illustrates levels of gene expression in different heart tissues for three groups of pigs having undergone biologic therapy using a viral gene therapy vector (i) without Impella support (pigs IGT5, IGT6, IGT12), (ii) with Impella support but without an angioplasty balloon (pigs IGT7, IGT8, IGT10), and (iii) with Impella support combined with an angioplasty balloon (pigs IGT4, IGT9, IGT11);

FIG. 2 illustrates levels of gene expression in left atrial tissue for the three groups of pigs of FIG. 1—the pigs having undergone biologic therapy using a viral gene therapy vector (i) without Impella support (pigs IGT5, IGT6, IGT12), (ii) with Impella support but without an angioplasty balloon (pigs IGT7, IGT8, IGT10), and (iii) with Impella support combined with an angioplasty balloon (pigs IGT4, IGT9, IGT11);

FIG. 3 illustrates levels of gene expression in liver tissue for the three groups of pigs of FIG. 1—the pigs having undergone biologic therapy using a viral gene therapy vector (i) without Impella support (pigs IGT5, IGT6, IGT12), (ii) with Impella support but without an angioplasty balloon (pigs IGT7, IGT8, IGT10), and (iii) with Impella support combined with an angioplasty balloon (pigs IGT4, IGT9, IGT11);

FIG. 4 illustrates vector genome expression for one pig (pig IGT11) having undergone biologic therapy using a viral gene therapy vector with Impella support and an angioplasty balloon, using PCR to count the vector genome and pig genome;

FIG.5 illustrates vector genome expression for one pig (pig IGT11) having undergone biologic therapy using a viral gene therapy vector with Impella support and an angioplasty balloon, assuming a certain weight of DNA per pig cell; and

FIG. 6 illustrates for different tissue samples a correlation between luciferase activity and vector genome expression for one pig (pig IGT11) having undergone biologic therapy using a gene therapy vector with Impella support and an angioplasty balloon.

DETAILED DESCRIPTION

To provide an overall understanding of the systems and methods described herein, certain illustrative implementations will be described. Although the implementations and features described herein are specifically described for use in connection with a circulatory and reperfusion therapy system, it will be understood that all the components and other features outlined below may be combined with one another in any suitable manner and may be adapted and applied to other types of circulatory therapy and reperfusion therapy devices.

As noted above, in one embodiment a gene therapy vector is introduced into an occluded vessel of a mechanically supported heart. FIGS. 1-6 illustrate results obtained in a gene therapy vector study performed on pigs. For a first control group of pigs. Pigs in the study were numbered-pig 5 being referred to as IGT5, pig 6 being referred to as IGT6, etc. Three groups of pigs were considered. In a first control group of pigs (“Group 1”), an adeno-associated virus type 6 vector (AAV6) with Luciferase (an enzyme producing bioluminescence) was injected into a coronary—no angioplasty balloon or mechanical circulatory system device was used. In a second group of pigs (“Group 2”), the left ventricle was unloaded with a mechanical circulatory system device (an Impella pump) while the gene therapy vector was injected into the coronary—no angioplasty balloon was used. In a third group of pigs (“Group 3”), an angioplasty balloon was deployed in the coronary, the gene therapy vector was injected into the coronary distal of the balloon, and a mechanical circulatory system device (an Impella pump) was used concurrently with the injection. As part of the study protocol, gene therapy vector injection was performed in phases—with a first injection phase followed by a period with no injection, then a second injection phase followed by a period with no injection, and finally a third injection phase followed by a period with no injection.

FIG. 1 illustrates results obtained during the pig study for the three groups of pigs. The Y axis measures Luciferase levels in tissue biopsies, with Luciferase levels being correlated to a number of genes expressed in the myocyte. If Luciferase is expressed, the assay glows, and the intensity of the glow is correlated to the amount of vector genome expressed in the tissue. The Y-axis uses a logarithmic scale, with a value of 1 indicating standard genome expression. The various data points (posterior, post endo, post epi, Apex, infarct, border) correspond to different regions of the heart muscle in which biopsies were taken. As shown in FIG. 1, compared to Group 1 (No Impella), and Group 2 (Impella but no balloon), the pigs in Group 3 (Balloon and Impella) show levels of vector genome expression which are logarithmically higher than the levels of vector genome expression for Group 1 or Group 2. At least one advantage of the concurrent use of the angioplasty balloon and the mechanical circulatory support device is the ability to prolong the time that the gene therapy vector medium is pooled in the myocardium, while maintaining cardiac stability. Deployment of the angioplasty balloon is relatively short, e.g. less than one (1) minute—occlusion of the coronary may result in some myocardial stunning (brief moments of tissue ischemia) but the effects of myocardial stunning are reversible.

FIG. 2 illustrates levels of vector genome expression, in a format similar to FIG. 1, but for left atrial tissue biopsies. As shown in FIG. 2, of Group 3, one pig—Pig 11 (IGT11)—had a 3000 fold increase in luciferase activity, indicating extremely high level of gene expression.

FIG. 3 illustrates levels of vector genome expression in a format similar to FIG. 1, but for liver tissue biopsies. When using a biologic therapy that deploys a virus vector, minimizing a presence of the virus outside of the target organ is desirable. Preferably, levels of the virus in a patient's systemic circulation should be low. Organs such as the liver, which are intended to clear systemic circulation indicate an extent to which the virus was evacuated from the system prior to reaching the liver. As shown in FIG. 3, for pigs of Group 3, levels of expression in the liver are lower than the expected expression value of 1. This indicates that most of the vector virus is output near the injection site—i.e. into the heart muscle, with only desirably low amounts of the vector virus reaching the liver.

FIG. 4 illustrates levels of vector genome expression for pig 11 of the same pig study but in a different format than FIGS. 1-3. FIG. 4 shows results of a biologic therapy that deploys a gene therapy vector using a PCR test—a polymerase chain reaction test. The results of the therapy that deployed a gene therapy vector for pig 11 (part of Group 3: Impella and angioplasty balloon use) using PCR are consistent with the results shown in FIGS. 1-3: pig 11 (and pigs of group 3) exhibits significantly higher levels of vector gene expression in certain heart tissues than in the rest of its system. In the left-hand side graph, the y-axis measures gene expression via PCR, and the x-axis corresponds to different biopsies from different tissue areas. PCR levels are much higher for tissue areas corresponding to the heart (Apex, Infarct, Border, Post epi, Post endo, Mid-septum, Base-ante, Base-lat, Base-post, Base-septum, coronary and left atrium) than they are for other tissue areas (RV, RA, Liver, SKM, Lung, Kidney cortex, spleen, brain, CM, non-CM). This confirms that the vast majority of the gene therapy vector is being expressed in the heart tissue, and other organs have very low expression. Similarly, in the right-hand side graph, a ratio of vector genome normalized by the pig genome for pig 11 (IGT11) is significantly higher in the coronary and left atrium tissue biopsies than it is in any other tissue biopsy (brain, CM, kidney, liver, lung, non CM, RV, SKI, spleen).

FIG. 5 displays another indicator of the gene therapy vector expression for the pig study. The therapy vector genome is normalized by the amount of DNA in a pig cell, assuming there are 6pg of DNA/pig cell. Again, ratios of therapy vector genome to pig genome are highest in the left atrium and coronary tissue biopsies, indicating that the left atrium and coronary are where the gene therapy vector is most efficient.

FIG. 6 illustrates a correlation between both types of gene therapy vector indicators considered in FIGS. 1-3 (Luciferase) and in FIGS. 4-5 (PCR). FIG. 6 maps luciferase activity on the y-axis and a ratio of vector genome/swine genome on the x-axis. FIG. 6 confirms that luciferase activity is directly related to viral genome (VG) expression. The higher the ratio of vector genome to swine genome, the higher the luciferase (Luc) activity.

The same technique described above with regard to a gene therapy vector may be used to increase uptake of other biologics including stem cells, RNA, mRNA, antisense oligonucleotide therapies, polypeptides, or any other biologic for intake in the heart. For example, the method can be used with oligonucleotides to interfere with gene production in the heart, or any other molecule with similar function. In another example, biologics targeted to manage or inhibit the inflammatory response of cardiac tissue may be injected into the heart, such as proprotein convertase subtilisin kexin type 9 (PCSK9), tumor necrosis factor (TNF) inhibitor, or RNA interference biologics. The treatment of heart disease and cardiac symptoms can be improved through intracoronary injection of various biologics to the myocardium or any other targets tissues type such as fibroblasts or endothelial cells. Biologic therapies can be adapted to preferentially target myocytes, fibroblasts, endothelial cells or other target tissues.

The biologic therapy is administered within a blood vessel in the heart, and may be administered in combination with the use of an angioplasty balloon in the blood vessel to temporarily occlude the vessel. The biologic therapy may be administered at a location in the heart distal of the angioplasty balloon, for example in the coronary artery distal of the angioplasty balloon. In some examples, the biologic therapy is administered over the course of several periods, interspersed with rest periods during which the biologic therapy is not administered. The rest period may be longer than the periods of administration of the biologic therapy.

Biologics can be injected into the heart in combination with each other or in combination with gene vector therapies, as indicated by the cardiac symptoms. For the delivery of any biologic to the myocardium or any other targeted tissues type such as fibroblasts or endothelial cells, the blood flow within a vessel is temporarily blocked to increase uptake of the biologic in the cardiac tissue and reduce clearance of the biologic through the heart while concurrently operating a mechanical circulatory support device in the heart to maintain heart function and systemic circulation without adverse effect to the patient. By blocking the blood flow during administration of the biologic, the biologic has more time in contact with the cardiac tissue to transduce the desired tissue target.

In this specification, the word “comprising” is to be understood in its “open” sense, that is, in the sense of “including”, and thus not limited to its “closed” sense, that is the sense of “consisting only of”. A corresponding meaning is to be attributed to the corresponding words “comprise”, “comprised” and “comprises” where they appear.

While particular embodiments of this technology have been described, it will be evident to those skilled in the art that the present technology may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments and examples are therefore to be considered in all respects as illustrative and not restrictive. For example, whilst the disclosure has described the detection of movements such as hand/arm based gestures and roll-overs, the same principal is applicable to other large scale motions, such as user moving between a lying and a sitting position in bed (and vice versa), reaching for a specific target (a table lamp, or a respiratory apparatus) etc.

It will further be understood that any reference herein to subject matter known in the field does not, unless the contrary indication appears, constitute an admission that such subject matter is commonly known by those skilled in the art to which the present technology relates.

Claims

1. A method of treating a heart, comprising the steps of: operating a mechanical circulatory support device for a support period;occluding a blood vessel during the support period; andduring the support period, administering a biologic therapy to the heart.

2. The method of claim 1 wherein the mechanical circulatory support device is operated at a rate of one of at least 2.5 L/min of blood flow, at least 3.5 L/min of blood flow or at least 5 L/min of blood flow.

3. The method of one of claim 1 wherein the biologic therapy is administered within the occluded blood vessel.

4. The method of claim 3, further comprising the steps of: inserting an angioplasty balloon into a blood vessel; andinflating the angioplasty balloon to temporarily occlude the blood vessel.

5. The method of claim 4 wherein administering the biologic therapy to the heart comprises: administering the biologic therapy within a patient blood vessel at a location distal of the angioplasty balloon.

6. The method of claim 5 wherein the patient blood vessel is a coronary artery, and the biologic therapy is administered within the coronary artery downstream from the inflated angioplasty balloon.

7. The method of claim 4, wherein administering a biologic therapy to the heart comprises: administering a first dose of biologic therapy to the heart during a first administration period;waiting a first rest period; andadministering a second dose of biologic therapy to the heart during a second administration period.

8. The method of claim 7 wherein administering the biologic therapy comprises injecting the biologic therapy into a vessel.

9. The method of claim 4 wherein the inflated angioplasty balloon occludes the blood vessel for less than about three minutes.

10. The method of claim 4 wherein the inflated angioplasty balloon occludes the blood vessel for less than about one minute.

11. The method of claim 4, wherein the support period is one of greater than 10 minutes, greater than 15 minutes, greater than 20 minutes, or greater than 30 minutes.

12. The method of claim 5 wherein a duration of the biologic therapy is one of less than 10 seconds, less than 30 seconds, less than 1 minute, less than 3 minutes, or less than 5 minutes.

13. The method of claim 7 wherein the first rest period is greater than the first administration period.

14. The method of claim 7 wherein the first administration period is greater than the second administration period.

15. The method of claim 7 wherein the mechanical circulatory support device is operating during the first administration period, the first rest period, and the second administration period.

16. The method of claim 1 wherein the mechanical circulatory support device comprises a blood pump.

17. The method of claim 16 wherein the blood pump is a microaxial blood pump.

18. The method of claim 1 wherein administering the biologic therapy comprises injecting the biologic therapy into one of a coronary, a myocardium, fibroblasts, or endothelial cells.

19. The method of claim 1 wherein the mechanical circulatory support device is operated at a rate of one of at least 2.5 L/min of blood flow, at least 3.5 L/min of blood flow or at least 5 L/min of blood flow.

20. The method of claim 1 any one of the preceding claims wherein the biologic therapy is a gene therapy vector.

21. The method of claim 20 wherein administrating the gene therapy vector to the heart is configured to increase an expression of vector DNA in cardiac tissue.

22. A method of supporting a patient's heart, comprising the steps of: percutaneously inserting a blood pump into a patient and positioning the blood pump across an aortic valve of the patient's heart;operating the blood pump to unload a left ventricle of the patient's heart;occluding a vessel of the patient's heart; andconcurrently with the operating the blood pump and occluding the vessel, injecting a biologic therapy into a coronary of the patient.

23. The method of claim 22 wherein the vessel is occluded by: placing a balloon in a coronary artery of a patient; andinflating the balloon for a first period to block blood flow within the coronary artery during a first period.

24. The method of claim 22 wherein the biologic therapy is a gene therapy vector.

25. A method of upregulating gene expression in a patient's myocardium, comprising the steps of: placing a balloon in a coronary artery of a patient;inflating the balloon for a first period to temporarily block blood flow within the coronary artery during the first period;placing a blood pump into a heart of the patient and positioning the blood pump across an aortic valve of the heart;operating the blood pump in the heart of the patient during a second period; andduring the first period, injecting a gene therapy vector within the coronary artery at a location distal of the inflated balloon, anddeflating the balloon after the first period to restore blood flow within the coronary artery, wherein the first period occurs during the second period and the first period has a duration that does not cause permanent ischemia in cells of the patient's myocardium.

26. The method of claim 25 further comprising: during the second period, injecting the gene therapy vector within the coronary artery at the location distal of the inflated balloon.

27. The method of claim 26 further comprising: during a third period, injecting the gene therapy vector within the coronary artery at the location distal of the inflated balloon, wherein the third period is less than or equal to the second period.

28. The method of claim 25, wherein the duration of the first period is less than three minutes.

29. The method of claim 28 wherein the duration of the first period is less than one minute.

30. The method of claim 29, wherein the duration of the first period is less than thirty seconds.

31. A cardioprotective system comprising: a mechanical circulatory support device;a balloon catheter having an inflatable balloon with a proximal end and a distal end, and an inflation catheter in fluid connection with the proximal end of a balloon of the balloon catheter, the balloon configured to be inserted in a coronary artery of a patient for concurrent use with the mechanical circulatory support device;a delivery catheter for delivering a biologic therapy in vivo, the delivery catheter having a proximal end with an inlet opening configured to receive a solution containing the biologic therapy, a distal end with an outlet opening, and a tube extending between the proximal and distal ends of the delivery catheter; andwherein the balloon is configured to occlude blood flow at least partially through the coronary artery when inflated.

32. The cardioprotective system of claim 31, wherein the mechanical circulatory support device is a catheter-based intravascular blood pump.

33. The cardioprotective system of claim 31, wherein the outlet opening of the distal end of the delivery catheter is configured to be positioned distal of the distal end of the inflatable balloon catheter when the balloon of the balloon catheter is inflated.

34. The cardioprotective system of claim 31, wherein the tube extending between the proximal and distal ends of the delivery catheter has a longitudinal length that is longer than the balloon.

35. The cardioprotective system of claim 31, wherein the balloon catheter is configured such that, upon balloon inflation, the delivery catheter outlet opening is not blocked by the balloon.

36. The cardioprotective system of claim 31 wherein the biologic therapy is a gene therapy vector.

37. The cardioprotective system of claim 36 wherein the gene therapy vector comprises non-native nucleic acid material that codes for a peptide that has a cardioprotective function when expressed in vivo, the gene therapy vector being configured to be absorbed by myocardial cells.

38. A method of supporting a patient's heart comprising: operating a mechanical circulatory support device while occluding a blood vessel; andadministering, during occlusion, a gene therapy vector within the patient's heart and at least one of the steps of:(i) reducing s rate of clearance of the gene therapy vector through the patient's heart;(ii) causing expression of the gene therapy vector in the patient's heart; and(iii) causing transduction of the patient's heart by the gene therapy vector.

39. The method of claim 38 wherein a balloon catheter is used to occlude the blood vessel.