Myoblast Transplantation for MI and CHF Treatment
Cell- and gene-based therapies show promise in treating cardiovascular disease.
Cell- and gene-based therapies hold tremendous potential to treat cardiovascular disease, however, significant obstacles need to be overcome before potential benefits are realized. There is no doubt that intracoronary or direct injection of either cells or genes into small animal models (mouse, rat, hamster, or rabbit) for heart disease produces improvements in cardiac function.1 The challenges, however, to treat human heart disease are far greater than in experimental animal systems. Key among the challenges is the mode of delivery for the therapeutic agent. For the purposes of this review, we will focus on cell-based therapies, however, most of the conclusions can be generalized to gene therapy applications as well.
CHOICE OF THERAPEUTIC CELL
An array of different cell types have been used in animal models and in preliminary human clinical trials, and several comprehensive reviews detail recent progress in this area.2,3 The ultimate effectiveness of any cell therapy will have to be demonstrated in well-controlled human clinical studies. From the accumulated knowledge to date in the emerging specialty of cell therapy, we can state several criteria that must be met to achieve success: (1) the cell population used needs to be prepared under controlled, well-defined procedures that guarantee consistent, viable cell isolates; (2) sufficient numbers of cells need to be delivered to or make their way to the site of damage; (3) cells must provide for sufficient repair and remodeling to sustain long-term (not just transient) recovery; (4) a reasonable cell dose based on the size of the infarct to be treated needs to be established; and (5) the fate of the cells injected needs to be determined (ie, where do the cells go and what do they become?). With these criteria in mind, we have chosen autologous skeletal myoblasts as the ideal cells for cardiac repair. Extensive experimentation in multiple labs around the world has repeatedly shown that autologous skeletal myoblasts can be consistently isolated and expanded in vitro, survive in both acute and chronic injury models, engraft and repair damaged myocardium in a predictable manner proportionate to the cell dose delivered, are safe, and provide for long-term benefit.2,4
METHOD OF INJECTION
There have been conflicting reports regarding the effectiveness of different routes of cell administration. The method that delivers the greatest consistency and reliability is direct injection into the heart muscle during an open chest procedure under visual guidance.5-9 Both the location of the infarct and confirmation of successful injection are best ensured by direct visualization. However, an open heart procedure is not the most practical method for injection of cells. Initially, the treatment would be limited to patients already undergoing an open heart procedure, and benefits due to the cell transplant would be difficult to separate from the effects of concomitant procedures, which has been the experience in several clinical studies using direct injection of cells into the surface of the heart. All of these studies have shown significant patient improvements, but it has been difficult to ascribe those improvements to the engraftment of the cells.5-9 Any future studies would have to be designed to control for improvements due to concomitant procedures. Furthermore, fewer patients undergo open heart procedures, severely restricting the number of patients eligible to benefit from such a therapy. Some alternate forms of cell delivery, such as intracoronary, intravenous, or endocardial injection, would be to a greater extent more practical and applicable for a much larger population of patients.
For any cell therapy to be effective, adequate numbers of cells must be delivered to the site of damage and the delivery of those cells must be repeatable and safe. Endocardial delivery of cells has consistently been shown to be a safe and effective way to deliver cells to an infarct.10-15 Intravenous delivery, although convenient and rapid, suffers from low efficiency of delivery to the specific site of damage. Cell-tracking studies show that a barely detectible number of cells find their way to the site of damage in the heart after intravenous administration, with the majority of the cells trafficking to the spleen and lungs.16 Likewise, intracoronary delivery suffers from poor efficiency of cell delivery, although results show efficiencies greater than that achieved through the intravenous route. Intracoronary delivery, however, presents safety concerns for the recipient in some instances. Studies have shown the potential for microembolization in the coronary circulation created by cells too large to pass into the venous system.17 In such cases, the cells could actually cause damage in addition to the infarct they were intended to treat. Because the potential for microembolization is dependent on the cells that are delivered, the potential risks and benefits for a particular cell type and mode of delivery will need to be tested empirically. Endoventricular cell delivery, unlike intravenous or intracoronary, provides safe, targeted and the highest efficiency of cell delivery to the area of infarct.18 Although repeated studies have shown that intraventricular delivery is a safe and effective means for cell delivery, not all injection catheter systems are as equally safe and effective.
CATHETER INJECTION METHODS
There are now multiple options for the intraventricular injection of cells or gene therapy agents (Table 1). All of them have been shown effective in animal studies, but compatibility issues between catheters and the agent being delivered have been observed.19 Therefore, caution is warranted before choosing a catheter system. The best option is to conduct detailed studies that give quantitative data about the effectiveness of a given therapeutic agent delivered with a given catheter system. Finally, because there are limits to the animal models used for testing safety and effectiveness of intraventricular delivery methods, the ultimate safety and effectiveness of delivery has to be demonstrated in clinical studies.
CURRENT MYOBLAST CLINICAL STUDIES
There are multiple ongoing or recently completed clinical studies utilizing autologous skeletal myoblasts (Table 2). We describe our current clinical study for the intraventricular catheter injection of myoblasts, which is an extension of the largest series of clinical studies with myoblasts performed in the US. Currently, a randomized study of 24 patients with congestive heart failure (New York Heart Association Classification III-IV) due to previous myocardial infarction is in progress at the Arizona Heart Institute. Patients are randomized 1:1 to undergo percutaneous endomyocardial autologous myoblast transplantation (treatment) and maximal medical therapy, or continue on maximal medical therapy only (control). The cells are injected percutaneously into the endoventricular surface of the previously infarcted left ventricle using 3D mapping and injection system (NOGA, Biosense Webster, Inc., a Johnson & Johnson company, Diamond Bar, CA; and MyoStar, Cordis Corporation, a Johnson & Johnson company, Miami, FL).
Treatment patients are monitored as in-patients during the transplantation procedure and for the first 24 hours. Vital signs and cardiovascular parameters are extensively monitored during the first 24 hours to determine the acute feasibility and safety of the transplantation procedure. The patients are then monitored over a period of 12 months to determine the long-term safety and efficacy of transplants.
To date, six of the planned 24 patients have been enrolled (three control and three treatment). The transplants have been well tolerated, and the injection procedures have all been successful and without complications. Figure 1A shows the NOGA map from one of the study patients before transplantation, followed by a map of the same patient 3 months after the procedure (Figure 1B). Significant changes are noted that suggest renewed tissue at the site of the implant. We will continue to enroll and test more patients to determine if the findings are consistent with the changes seen in this patient population, and, if results are confirmed, we plan to conduct a phase 2 randomized, double-blind, placebo-controlled study to best test for efficacy of the myoblast transplants.
Jonathan Dinsmore, PhD, is Chief Scientific Officer for Mytogen, Inc. in Charlestown, Massachusetts. He has disclosed that he is salaried by and a shareholder in Mytogen, Inc. Dr. Dinsmore may be reached at (617) 242-9100; email@example.com.
Nabil Dib, MD, is Director of Cardiovascular Research at the Arizona Heart Institute in Phoenix, Arizona. He has disclosed that he is a paid consultant for and shareholder in Mytogen, Inc. Dr. Dib may be reached at 602-266-2200; firstname.lastname@example.org.
1. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005;115:572-583.
2. Dinsmore JH, Dib N. An overview of myoblast transplantation for myocardial regeneration. Am Heart Hosp J. 2005;3:146-152.
3. Murry CE, Field LJ, Menasche P. Cell-based cardiac repair: reflections at the 10-year point. Circulation. 2005;112:3174-3183.
4. Menasche P. Skeletal muscle satellite cell transplantation. Cardiovasc Res. 2003; 58:351-357.
5. Dib N, McCarthy P, Campbell A, et al. Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy. Cell Transplant. 2005;14:11-19.
6. Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J. 2003;24:2012-2020.
7. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol. 2003;41:1078-1083.
8. Pagani FD, DerSimonian H, Zawadzka A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol. 2003;41:879-888.
9. Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J. 2004;148:531-537.
10. Amado LC, Saliaris AP, Schuleri KH, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA. 2005;102:11474-11479.
11. Dib N, Campbell A, Jacoby DB, et al. Safety and feasibility of percutaneous autologous skeletal myoblast transplantation in the coil-infarcted swine myocardium. J Pharmacol Toxicol Methods. 2006. In Press.
12. Dib N, Diethrich EB, Campbell A, et al. Endoventricular transplantation of allogenic skeletal myoblasts in a porcine model of myocardial infarction. J Endovasc Ther. 2002;9:313-319.
13. Garot J, Unterseeh T, Teiger E, et al. Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol. 2003;41:1841-1846.
14. Kornowski R, Fuchs S, Tio FO, et al. Evaluation of the acute and chronic safety of the biosense injection catheter system in porcine hearts. Catheter Cardiovasc Interv. 1999;48:447-453; discussion 454-455.
15. Rezaee M, Yeung AC, Altman P, et al. Evaluation of the percutaneous intramyocardial injection for local myocardial treatment. Catheter Cardiovasc Interv. 2001;53:271-276.
16. Hofmann M, Wollert KC, Meyer GP, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111:2198-2202.
17. Vulliet PR, Greeley M, Halloran SM, et al. Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet. 2004;363:783-784.
18. Hayashi M, Li TS, Ito H, et al. Comparison of intramyocardial and intravenous routes of delivering bone marrow cells for the treatment of ischemic heart disease: an experimental study. Cell Transplant. 2004;13:639-647.
19. Marshall DJ, Palasis M, Lepore JJ, et al. Biocompatibility of cardiovascular gene delivery catheters with adenovirus vectors: an important determinant of the efficiency of cardiovascular gene transfer. Mol Ther. 2000;1(5 Pt 1):423-429.
20. Chazaud B, Hittinger L, Sonnet C, et al. Endoventricular porcine autologous myoblast transplantation can be successfully achieved with minor mechanical cell damage. Cardiovasc Res. 2003;58:444-450.
21. Kornowski R, Leon MB, Fuchs S, et al. Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy. Results in normal and ischemic porcine models. J Am Coll Cardiol. 2000;35:1031-1039.
22. Grossman PM, Han Z, Palasis M, et al. Incomplete retention after direct myocardial injection. Catheter Cardiovasc Interv. 2002;55:392-397.
23. Ince H, Petzsch M, Rehders TC, et al. Transcatheter transplantation of autologous skeletal myoblasts in postinfarction patients with severe left ventricular dysfunction. J Endovasc Ther. 2004;11:695-704.
24. Smits PC, van Geuns RJ, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol. 2003;42:2063-2069.
25. Siminiak T, Fiszer D, Jerzykowska O, et al. Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. Eur Heart J. 2005;26:1188-1195.
26. Thompson CA, Reddy VK, Srinivasan A, et al. Left ventricular functional recovery with percutaneous, transvascular direct myocardial delivery of bone marrow-derived cells. J Heart Lung Transplant. 2005;24:1385-1392.
27. Dib N, Michler RE, Pagani FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation. 2005;112:1748-1755.