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.

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; and during 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; and inflating 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; and administering 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; and concurrently 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; and inflating 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; and during the first period, injecting a gene therapy vector within the coronary artery at a location distal of the inflated balloon, and deflating 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; and wherein 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; and administering, 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.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0012] 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:

[0013] 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);

[0014] FIG. 2 illustrates levels of gene expression in left atrial tissue for the three groups of pigs of FIG. 1the 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);

[0015] FIG. 3 illustrates levels of gene expression in liver tissue for the three groups of pigs of FIG. 1the 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);

[0016] 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;

[0017] 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

[0018] 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

[0019] 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.

[0020] 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 coronaryno 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 coronaryno 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 phaseswith 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.

[0021] 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) minuteocclusion of the coronary may result in some myocardial stunning (brief moments of tissue ischemia) but the effects of myocardial stunning are reversible.

[0022] 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 pigPig 11 (IGT11)had a 3000 fold increase in luciferase activity, indicating extremely high level of gene expression.

[0023] 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 sitei.e. into the heart muscle, with only desirably low amounts of the vector virus reaching the liver.

[0024] 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 testa 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).

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.