Systems and methods for unloading the left ventricle in biological or vector gene therapy

Abstract

To provide methods and systems for using mechanical circulatory support concurrently with a biologic therapy (e.g., a gene therapy vector).SOLUTION: Particular adaptation includes a cardiac therapy method comprising: occluding a blood vessel such as a coronary artery; injecting a gene therapy vector or biologic to a site distal to the occlusion site; and waiting for a certain amount of time; while using the mechanical circulatory support system to provide circulatory support to a patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 62 / 826,444, filed March 29, 2019, and 62 / 959,333, filed January 10, 2020, both of which are incorporated herein by reference. [Background technology]

[0002] background Cardiovascular disease is the leading cause of morbidity, mortality, and healthcare burden worldwide. Various treatment modalities for cardiovascular disease have been developed, ranging from pharmaceuticals to medical devices and ultimately transplantation. Temporary cardiac assist devices, such as ventricular assist devices, provide hemodynamic support and promote cardiac recovery. Ventricular assist devices, such as the IMPELLA® family of devices (Abiomed, Inc., Dunbar, Massachusetts), are also inserted percutaneously into the heart and can supplement cardiac output by working alongside the native heart.

[0003] Genetic manipulation can be used to target genes and treat cells or organs such as the heart. See, for example, Julie A. Wolfram, PhD et al., Gene Therapy to Treat Cardiovascular Disease, JAHA Vol. 2, Issue 4 (2013) ("Wolfram"), the entire text of which is incorporated herein by reference. Gene therapy methods include the use of one or more gene therapy vectors, whether viral or non-viral. In the case of viral vectors, the genome of a virus can be programmed and then injected into a patient as a gene therapy vector, with the expectation that the viral genome will be expressed in the patient. At least one example of a viral vector is the adeno-associated virus (AAV). Vectors can be administered by injection or perfusion at various locations. For example, coronary vascular perfusion can deliver the vector genome to the entire myocardium. Generally, high gene expression is required to achieve a therapeutic effect. At least one disadvantage of administering viral vectors to the coronary vessels is that the efficiency of this approach is relatively low due to the rapid delivery of the vector genome into the systemic circulation by the heart. Because of cardiac extrusion, the clearance rate of the vector genome from the heart may be too rapid to achieve the desired gene expression. The virus passes through the heart relatively quickly, leaving relatively little time to adhere to and adequately transduce the myocardium. This same problem arises when administering biological therapies to the heart. Arresting the heart to slow the clearance rate of the vector genome or biologic and allow prolonged retention in the heart can lead to cardiac instability and / or ischemia.

[0004] It would therefore be desirable to have a system and method that can reduce the rate of clearance of vector genomes and biologics in the heart without the downsides associated with stopping or slowing the heart. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Julie A. Wolfram, PhD et al., Gene Therapy to Treat Cardiovascular Disease, JAHA Vol 2, Issue 4 (2013) Summary of the Invention

[0006] overview The methods, systems, and devices described herein enable efficient delivery of biological therapies, such as, but not limited to, gene therapy vectors, to the myocardium by (i) temporarily blocking blood flow to the myocardium to increase myocardial absorption of the biological therapy (e.g., gene therapy vector) and reduce clearance of the biological therapy (e.g., gene therapy vector) from the heart, while simultaneously operating a mechanical circulatory assist device within the heart to maintain cardiac function and systemic circulation without adverse effects to the patient. At least one advantage of these methods, systems, and devices is their ability to increase the attachment of biological therapies (e.g., gene therapy vectors) within the myocardium. By temporarily stopping blood flow with an angioplasty balloon in at least one coronary vessel (i.e., the arteries and blood vessels surrounding and supplying the heart) and injecting a biological therapy, such as a gene therapy vector virus, distal to the deployed balloon, the viral vehicle pools within the coronary artery, allowing the viral vector or other therapy considerable time to transduce the myocardium. By injecting a biological therapy while activating a mechanical circulatory assist device, vital cardiac output is maintained and the patient is able to survive an ischemic event that an inflated angioplasty balloon might cause; in essence, the mechanical circulatory assist device acts as a temporary cardiac bypass. The mechanical assist device can be a blood pump, such as an Impella device. In some embodiments, a biological therapy, such as a gene therapy vector, can be targeted to specific cardiac tissues, such as fibroblasts or endothelial cells. In some embodiments, one or more gene therapy vectors can be used to preferentially target myocytes, fibroblasts, endothelial cells, or other target tissues.

[0007] In a first exemplary embodiment, a method of treating the heart includes operating a mechanical circulatory assist device to assist the heart. In some embodiments, the mechanical circulatory assist device is operated outside the patient's body, while in other embodiments, the mechanical circulatory assist device is inserted into the patient. The method further includes operating the mechanical circulatory assist device for an assisted period and administering a biological therapy, such as a gene therapy vector, to the heart during the assisted period. In one example, the gene therapy vector is administered into a blood vessel of the heart. In another example, the method further includes inserting an angioplasty balloon into the blood vessel and inflating the balloon to temporarily close the blood vessel. In one example, the gene therapy vector is administered to the heart at a location distal to the angioplasty balloon. For example, the gene therapy vector is administered downstream of the inflated balloon within a coronary artery. In some examples, the gene therapy vector may be administered over the course of several periods. For example, a first dose of the gene therapy vector is administered to the heart during a first administration period, followed by a second dose of the gene therapy vector 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 blood vessel for less than about 3 minutes, preferably 1 minute. In one example, the assistance period in which a mechanical circulatory assist device, such as a microaxial transvalvular pump, is used is longer than 10 minutes. The assist device is activated during these various administration and rest periods. In one example, administration of the gene therapy vector to the heart is configured to increase expression of the vector DNA in cardiac tissue. Tissues within the heart, such as myocardium, fibroblasts, endothelial cells, or other cardiac tissue, can be targeted with the gene therapy vector.

[0008] In a second exemplary embodiment, a method of assisting a patient's heart includes percutaneously inserting a blood pump into the heart and positioning the blood pump across the aortic valve of the heart. The method further includes operating the blood pump to unload the left ventricle of the heart, and simultaneously operating the blood pump, injecting a gene therapy vector into a coronary vessel of the heart that has been obstructed as described herein.

[0009] In a third exemplary embodiment, a method for upregulating gene expression in a patient's myocardium includes placing a balloon in a patient's coronary artery and inflating the balloon for a first period of time to temporarily block blood flow in the coronary artery for the first period of time. The method further includes placing a blood pump in the patient's heart and positioning the pump across the aortic valve of the heart, and then operating the blood pump in the patient's heart for a second period of time. The method includes injecting a gene therapy vector into the coronary artery at a location distal to the inflated balloon during the first period of time, and deflating the balloon after the first period of time to restore blood flow in the coronary artery. In this exemplary embodiment, the first period of time is within a second period of time, and the first period of time has a duration that does not cause permanent ischemia to cells of the myocardium. In one example, the method includes injecting a biologic therapy, such as a gene therapy vector, into the coronary artery at a location distal to the inflated balloon during the second period of time. In another example, the method includes injecting a gene therapy vector into the coronary artery distal to the inflated balloon for a third period of time that is shorter than or equal to the second period of time. The duration of the first period of time can be less than 3 minutes, preferably less than 1 minute.

[0010] In a fourth exemplary embodiment, a method of assisting a patient's heart includes administering a biological therapy, such as a gene therapy vector, into the heart. The method further includes reducing the clearance rate of the biological therapy, such as a gene therapy vector, from the heart. In embodiments where the biological therapy is a gene therapy vector, the reduced clearance rate results in expression of the gene therapy vector in the heart, transduction of the heart by the gene therapy vector, or any combination thereof. In one example, the method deploys a mechanical circulatory assist device and a balloon catheter in the heart.

[0011] In a fifth exemplary embodiment, a cardioprotection system for assisting the heart of a patient experiencing cardiogenic shock or myocardial infarction includes a mechanical circulatory assist device configured for insertion into the patient and for operation, and a balloon catheter having an inflatable balloon with a proximal end and a distal end. The balloon catheter includes an inflation catheter in fluid communication with the proximal end of the balloon, the balloon configured for insertion into the patient's coronary artery for simultaneous use with the mechanical circulatory assist device. The system further includes a delivery catheter for in vivo delivery of gene vector therapy, the delivery catheter having a proximal end with an inlet opening configured to receive a solution containing a 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 at least partially occlude blood flow through the coronary artery when inflated. In one example, the mechanical circulatory assist device is a catheter-based intravascular blood pump. In another example, the outlet opening is configured to be located distal to the distal end of the balloon when inflated. In yet another example, the tube extending between the proximal and distal ends of the delivery catheter has a longitudinal length longer than the balloon. In another example, the balloon catheter is configured such that the balloon does not obstruct the exit opening of the balloon catheter upon inflation. In aspects in which a gene therapy vector is administered, the vector can include a non-naturally occurring nucleic acid material encoding a peptide that has cardioprotective function when expressed in vivo, and the gene therapy vector is configured to be taken up by cardiomyocytes.

[0012] In a sixth exemplary embodiment, a method of treating the heart includes activating a mechanical circulatory assist device to assist the heart. The method further includes activating the mechanical circulatory assist device for an assistance period, occluding at least one cardiac vessel, and administering a biological therapy to the occluded cardiac vessel. The biological therapy may preferentially target myocytes, fibroblasts, endothelial cells, or other target tissue. [Brief explanation of the drawings]

[0013] The foregoing and other objects and advantages will become apparent from the following detailed description considered in conjunction with the accompanying drawings, in which like reference numerals refer to like parts throughout.

[0014] [Figure 1] Illustrates gene expression levels in various cardiac tissues from three groups of pigs that underwent biologic therapy using viral gene therapy vectors: (i) without Impella support (pigs IGT5, IGT6, IGT12), (ii) with Impella support but without angioplasty balloon (pigs IGT7, IGT8, IGT10), and (iii) with Impella support combined with angioplasty balloon (pigs IGT4, IGT9, IGT11). [Figure 2] Gene expression levels in left atrial tissue from three groups of pigs are illustrated in Figure 1. Pigs received 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). [Figure 3] Gene expression levels in liver tissue from three groups of pigs are illustrated in Figure 1. Pigs received biologic therapy using viral gene therapy vectors (i) without Impella support (pigs IGT5, IGT6, IGT12), (ii) with Impella support but without angioplasty balloon (pigs IGT7, IGT8, IGT10), and (iii) with Impella support combined with angioplasty balloon (pigs IGT4, IGT9, IGT11). [Figure 4] Vector genome expression is illustrated in one pig (pig IGT11) that underwent biologic therapy using a viral gene therapy vector with Impella assistance and angioplasty balloon, as measured by PCR of the vector genome and pig genome. [Figure 5]Illustrates vector genome expression in one pig (pig IGT11) undergoing biologic therapy using a viral gene therapy vector with Impella assistance and angioplasty balloon, assuming a constant DNA weight per pig cell. [Figure 6] Illustrates the correlation between luciferase activity and vector genome expression in various tissue samples from one pig (pig IGT11) that underwent biologic therapy using a viral gene therapy vector with Impella assistance and angioplasty balloon. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description To provide an overall understanding of the systems and methods described herein, certain exemplary embodiments will be described. While the embodiments and features described herein are described specifically for use in connection with circulation and reperfusion therapy systems, it will be understood that any of the components and other features outlined below may be combined with one another in any suitable manner and may be adapted or applied to other types of circulation and reperfusion therapy devices.

[0016] As mentioned above, in one embodiment, a gene therapy vector is introduced into the blocked vessels of a mechanically supported heart. Figures 1-6 illustrate results from a gene therapy vector study conducted in pigs. Regarding the first control group of pigs, pigs were numbered as follows: pig 5 was designated IGT5, pig 6 was designated IGT6, and so on. Three groups of pigs were considered. In the first control group of pigs ("Group 1"), adeno-associated viral vector type 6 (AAV6) and luciferase (an enzyme that produces bioluminescence) were injected into the coronary vessels, without the use of an angioplasty balloon or mechanical circulatory system device. In the second group of pigs ("Group 2"), the left ventricle was unloaded with a mechanical circulatory system device (Impella pump), while the gene therapy vector was injected into the coronary vessels. An angioplasty balloon was not used. In a third group of pigs ("Group 3"), an angioplasty balloon was deployed in the coronary vessels, and the gene therapy vector was injected into the coronary vessels distal to the balloon using a mechanical circulatory system device (Impella pump) simultaneously with the injection. As part of the study protocol, the gene therapy vector injections were administered in phases, with a first injection phase followed by an injection-free period, a second injection phase followed by an injection-free period, and finally a third injection phase followed by an injection-free period.

[0017] Figure 1 illustrates the results observed for three groups of pigs during the porcine study. The y-axis is a measurement of the level of luciferase in the tissue biopsies, which correlates with several genes expressed in the myocytes. Luciferase expression causes the assay to light up, and the intensity of the light correlates with the amount of vector genome expressed in the tissue. The y-axis uses a logarithmic scale, with a value of 1 indicating normal genome expression. The various data points (posterior, post endothelial, post epithelial, apical, infarct, and margin) correspond to different regions of the myocardium from which the biopsies were taken. As shown in Figure 1, compared to groups 1 (no Impella) and 2 (with Impella and no balloon), pigs in group 3 (with balloon and Impella) exhibit logarithmically higher levels of vector genome expression than either group 1 or group 2. At least one advantage of using an angioplasty balloon and a mechanical circulatory assist device simultaneously is the ability to prolong the time that the gene therapy vector vehicle pools within the myocardium while maintaining cardiac stability. The duration of angioplasty balloon deployment is relatively short, e.g., less than one minute, and although some degree of myocardial stunning (brief tissue ischemia) may result from occlusion of the coronary vessels, the effects of myocardial stunning are reversible.

[0018] Figure 2, similar in format to Figure 1, illustrates the expression levels of the vector genome for left atrial tissue biopsies. As shown in Figure 2, one pig in Group 3, pig 11 (IGT11), had a 3000-fold increase in luciferase activity, indicating extremely high levels of gene expression.

[0019] Figure 3, similar in format to Figure 1, illustrates the expression level of vector genomes in liver tissue biopsies. When using biologic therapies employing viral vectors, it is desirable to minimize the presence of virus outside of the target organ. Preferably, virus levels in the patient's systemic circulation should be low. Organs such as the liver, which are intended to clear the systemic circulation, indicate how much virus was removed from the system before reaching the liver. As shown in Figure 3, in pigs from Group 3, the expression level in the liver was lower than the expected expression value of 1. This indicates that the majority of the vector virus was output near the injection site, i.e., into the myocardium, and that only a small amount of vector virus reached the liver, which is desirable.

[0020] Figure 4 illustrates the expression levels of vector genomes in pig 11 from the same pig study, but in a different format than Figures 1-3. Figure 4 shows the results of biologic therapy employing a gene therapy vector using PCR, or polymerase chain reaction, testing. The results of treatment with gene therapy vectors for pig 11 (one of group 3: treated with Impella and angioplasty balloon) by PCR are consistent with the results shown in Figures 1-3, with pig 11 (and pigs in group 3) demonstrating higher vector gene expression levels in specific cardiac tissues than in other parts of the system. In the graph on the left, the y-axis represents gene expression as measured by PCR, and the x-axis corresponds to different biopsies from different tissue areas. PCR levels are much higher in tissue areas corresponding to the heart (apex, infarct, margin, posterior epithelium, posterior endothelium, medial-septum, base-anterior, base-lateral, base-posterior, base-septum, coronary vessels, and left atrium) than in other tissue areas (RV, RA, liver, SKM, lung, renal cortex, spleen, brain, CM, and non-CM). This confirms that the majority of the gene therapy vector is expressed in cardiac tissue, with very little expression in other organs. Similarly, in the graph on the right, the proportion of vector genomes for porcine 11 (IGT11), normalized by the porcine genome, is significantly higher in coronary vessel and left atrial tissue biopsies than in any other tissue biopsies (brain, CM, kidney, liver, lung, non-CM, RV, SKM, and spleen).

[0021] Figure 5 displays another measure of gene therapy vector expression in the pig study. The therapy vector genome is normalized by the amount of DNA in a single pig cell, assuming 6 pg of DNA per pig cell. Again, the ratio of therapy vector genome to pig genome was highest in tissue biopsies from the left atrium and coronary vessels, indicating that the gene therapy vector is most efficient in these tissue biopsies.

[0022] Figure 6 illustrates the correlation between gene therapy vector indicators (luciferase) of the type discussed in Figures 1-3 and gene therapy vector indicators (PCR) of the type discussed in Figures 4-5. Figure 6 plots luciferase activity on the y-axis and the vector genome / pig genome ratio on the x-axis. Figure 6 confirms that luciferase activity is directly related to viral genome (VG) expression. The higher the ratio of vector genome to pig genome, the higher the luciferase (Luc) activity.

[0023] The same techniques described above for gene therapy vectors can be used to increase the uptake of other biologics, such as stem cells, RNA, mRNA, antisense oligonucleotide therapeutics, polypeptides, or any other biologics intended for cardiac uptake. For example, the methods can be used in conjunction with oligonucleotides that disrupt gene production in the heart, or any other molecules with similar functions. In another example, biologics targeted to manage or inhibit inflammatory responses in cardiac tissue, such as proprotein convertase subtilisin kexin type 9 (PCSK9), tumor necrosis factor (TNF) inhibitors, or RNA interference biologics, can be injected intracardially. Treatment of cardiac diseases and conditions can be improved by intracoronary injection of various biologics into the myocardium or any other target tissue type, such as fibroblasts or endothelial cells. Biologic therapies may be preferentially targeted to myocytes, fibroblasts, endothelial cells, or other target tissues.

[0024] The biologic therapy is administered intravascularly in the heart, and may be administered in conjunction with the use of an intravascular angioplasty balloon to temporarily occlude the blood vessel. The biologic therapy can be administered at a location distal to the intracardiac angioplasty balloon, for example, at a location distal to the angioplasty balloon in the coronary artery. In some instances, the biologic therapy is administered over the course of several periods separated by rest periods during which the biologic therapy is not administered. The rest periods may be longer than the periods during which the biologic therapy is administered.

[0025] Depending on cardiac symptoms, biologics can be injected into the heart in combination with each other or in combination with gene vector therapy.To deliver any biologic to myocardium or any other target tissue type, such as fibroblasts or endothelial cells, blood flow in blood vessels is temporarily blocked to increase the absorption of biologic in cardiac tissue and reduce the clearance of biologic from the heart, while simultaneously operating a mechanical circulatory assist device in the heart to maintain cardiac function and systemic circulation without adverse effects to patients.By blocking blood flow during the administration of biologic, the biologic can be allowed to contact cardiac tissue for a longer time for transduction into the desired tissue target.

[0026] In this specification, the word "comprising" is to be understood in the "broad sense", i.e., in the sense of "including", and therefore not limited to the "narrow sense", i.e., "consisting only of". The corresponding words "comprise", "comprised", and "comprises", where they appear, have corresponding meanings.

[0027] While specific embodiments of the technology have been described, it will be apparent to those skilled in the art that the technology may be embodied in other specific forms without departing from its essential characteristics. Accordingly, the embodiments and examples herein should be considered in all respects as illustrative and non-limiting. For example, while this disclosure has described detecting hand / arm-based gestures and rotational movements, the same principles can be applied to other large-scale movements, such as when a user moves from a lying position in bed to a sitting position (or vice versa), or when reaching for a specific target (such as a table lamp or breathing apparatus).

[0028] It will be further understood that reference herein to subject matter known in the art does not constitute an admission that such subject matter is well known to those skilled in the art, unless a contrary statement occurs.

Claims

1. a balloon catheter having an inflatable balloon having a proximal end and a distal end, the balloon catheter including a dilatation catheter in fluid communication with the proximal end of the balloon, the balloon catheter configured to be inserted into a coronary artery of a patient, the balloon catheter further configured to be inflated for a first period of time to at least partially occlude blood flow through the coronary artery of the patient, and to deflate the balloon after the first period of time to restore blood flow in the coronary artery; a mechanical circulatory assist device configured for placement in the patient's heart and configured to operate during a second time period, wherein the first time period occurs within a second time period and the first time period has a duration that does not result in permanent ischemia to cells of the myocardium; a delivery catheter having a proximal end with an inlet opening configured to receive a solution containing a biological agent, and a distal end with an outlet opening configured to deliver the biological agent to a coronary artery of the patient distal to the distal end of the balloon catheter during the first period of time; Cardioprotective system, including:

2. The system of claim 1 , wherein the delivery catheter is further configured to deliver a biological agent to the coronary artery distal to the balloon during the second period of time.

3. The system of claim 1 , wherein the first period of time is less than three minutes in length.

4. The system of claim 3 , wherein the first period of time is less than one minute in length.

5. The system of claim 4 , wherein the first period of time is less than 30 seconds in length.

6. 10. The system of claim 1, wherein the mechanical circulatory assist device is a microaxial transvalvular blood pump.

7. The system of claim 6 , wherein the microaxial transvalve blood pump is a catheter-based microaxial transvalve blood pump.

8. The system of claim 1 , wherein the delivery catheter includes a tube extending between a proximal end and a distal end.

9. The system of claim 8 , wherein the tube has a longer longitudinal length than the balloon.

10. The system of claim 1 , wherein the balloon catheter is configured such that the balloon does not obstruct the exit opening upon balloon inflation.

11. The system of claim 1 , wherein the biological agent is a gene therapy vector.

12. The system of claim 11 , wherein delivery of the gene therapy vector is configured to increase expression of the gene therapy vector in cardiac tissue.

13. The system of claim 12, wherein the gene therapy vector comprises a non-natural nucleic acid substance encoding a peptide that has cardioprotective function when expressed in vivo and is configured to be taken up by cardiomyocytes.

14. The system of claim 1 , wherein the first period of time has a duration of less than 1 minute or less than 3 minutes.

15. 3. The system of claim 2, wherein the delivery catheter is configured to deliver the biological agent to the coronary artery at a location distal to the balloon for a third period of time, the third period of time being less than or equal to the second period of time.

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