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Innovations: Technology & Techniques in Cardiothoracic & Vascular Surgery:
doi: 10.1097/IMI.0b013e318265d9f6
Review Article

Cardiac Biointerventions: Whatever Happened to Stem Cell and Gene Therapy?

Rosengart, Todd K. MD*†; Fallon, Eleanor BS; Crystal, Ronald G. MD

Free Access
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Author Information

From the *Division of Cardiothoracic Surgery, Department of Surgery, †Stony Brook University Medical Center, Stony Brook, NY USA; and ‡Department of Genetic Medicine, Weill Cornell Medical College, New York, NY USA.

Accepted for publication June 20, 2012.

Presented at the Annual Scientific Meeting of the 21st Century Cardiothoracic Surgical Society, February 17–19, 2012, Boca Raton, FL USA.

Disclosure: The authors declare no conflict of interest.

Address correspondence and reprint requests to Todd K. Rosengart, MD, Division of Cardiothoracic Surgery, Department of Surgery, Stony Brook University Medical Center, Health Sciences Center T19-020, Stony Brook, NY 11794-8020 USA. E-mail: todd.rosengart@stonybrookmedicine.edu.

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Abstract

Abstract: Angiogenic gene therapy and stem cell administration represent two “biologic” interventions for the treatment of cardiac disease that were first introduced more than 15 years ago but still have not achieved approval for clinical use for the treatment of myocardial ischemia and heart failure. Challenges that have been encountered in the clinical testing of these new treatment strategies have included a lack of placebo controls in phase I surgical trials and the incorporation of potentially ineffectual agent delivery via intracoronary routes. Although enthusiasm for these approaches may therefore have ebbed, new refinements in these technologies and insights into their appropriate clinical testing suggest that a resurgence of interest in these “biointerventions” may be expected in the near future.

Many hundreds of individuals were enrolled in dozens of clinical trials in the late 1990s and the first half of the past decade exploring “biologic” means of treating cardiac disease. Predominantly, these studies not only involved (angiogenic) gene therapy and stem cell interventions but also included gene therapy for the treatment of heart failure, protein-based interventions for inducing myocardial revascularization, and even mechanical (laser) means of creating transmyocardial revascularization (TMR).1–6 These trials have largely disappeared from the agenda of scientific meetings, none have advanced to approvals for commercial use (with the exception of TMR), and enthusiasm for these fields of investigation has significantly dissipated from the lay and scientific community. What has happened? Are these “biointerventions” a clinical failure, has the initial enthusiasm simply waned, or is work still ongoing? These are all true, to a degree.

To understand the current state of the field, it is first important to consider that both gene therapy and stem cell therapy were greeted with an almost unrealistic enthusiasm when they first appeared in the clinical arena. As detailed below, these interventions were translated from animal studies into clinical trials with what, in retrospect, seems to have been a significant disregard for the basic tenet of new drug testing: the diligent incorporation of the pharmacokinetics and bioactivity of candidate agents into a careful and probative trial design. In part, these lapses may have occurred because this new class of therapy was imbued with almost magical properties that negated these standard principles of drug testing, whereas in reality, these agents—gene transfer vectors and stem cells—were no more than a new generation of biologics. Unfortunately, support for these innovative cardiac treatments rapidly collapsed when the initially hyperbolic enthusiasm for these potential new modalities encountered the reality of failed trials, regardless that many of these trials were likely destined to failure, as discussed below, because of their improper conception and design.

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CARDIAC GENE THERAPY AND THERAPEUTIC ANGIOGENESIS

The new era of cardiac biointervention was ushered in during the late 1990s with a series of phase I “therapeutic angiogenesis” trials designed to revascularize the myocardium of “no option” patients with diffuse coronary disease not amenable to conventional interventions and with symptomotology refractory to medical therapy.7–14 These small, phase I trials involved several different angiogenic peptides (eg, vascular endothelial growth factor [VEGF]-121, VEGF-165, VEGF-2, fibroblast growth factor) that were delivered to ischemic myocardium via a variety of methodologies (typically via intracoronary or direct myocardial administration of protein, plasmids, or viral vectors). Similar studies were conducted for peripheral vascular disease and coincided with the advent of laser-based TMR for treatment of the same population.6,15,16

Whereas nearly all of these phase I trials yielded promising results, subsequent, larger randomized controlled trials (RCTs) generally failed to demonstrate efficacy.17–20 The explanation for these failures may be rooted in the need for investigators to incorporate a placebo control in these trials. This objective led investigators to choose relatively noninvasive approaches, such as intracoronary delivery strategies, to mitigate ethical concerns associated with the use of placebo controls by potentially less well-tolerated surgical delivery. Unfortunately, intracoronary administration had already been shown to yield very low uptake by the target myocardium compared with direct myocardial delivery,21 and these trials likely proved ineffective because of subtherapeutic agent administration to target tissues.1,2,4 In alternative trial designs, a catheter-based endocardial delivery methodology was used to allow for placebo controls and theoretically more effective direct myocardial vector delivery to target tissues using this minimally invasive approach.22–24 Unfortunately, these trials also failed to demonstrate efficacy, likely because these remote delivery strategies also yielded low total “drug” delivery to the myocardium.24,25

Careful analysis of these pharmacokinetic considerations should have suggested that the negative outcomes of the intracoronary and catheter-based trials were to be expected. Instead, the results of these larger “pivotal” trials were extrapolated to the field in general, including the (surgical) trials using direct myocardial delivery under direct vision that had, in contrast, yielded some evidence of efficacy (Tables 1 and 2). The lack of placebo controls in the surgical trials nevertheless led critics to dismiss the data from these studies as invalidated by a potential placebo effect,28 despite the inclusion of objective endpoints (eg, “time to 1 mm ST depression” on exercise treadmill). As a result, because the only RCTs in the field had yielded negative results, the field was largely abandoned, despite the potential design flaws in these RCTs.

Table 1
Table 1
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Table 2
Table 2
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To address these issues, we recently proposed and received unanimous approval from the National Institutes of Health Recombinant Advisory Committee to perform a randomized, placebo-controlled trial using what we believe to be an appropriate delivery strategy—direct myocardial administration via a surgical approach (minithoracotomy)—and using a “nontherapeutic” adenovirus with an empty expression cassette (AdNull) as a placebo control arm in a 3:1 randomization protocol.29 As a further improvement on previous studies, we plan to incorporate a “genomic” angiogenic cassette (VEGF-All6A+) that expresses all three isoforms of VEGF (121, 165, and 189) more potently than our VEGF-121 vector,30 mimicking the endogenous expression of the VEGF gene to enhance the efficacy of this intervention (Fig. 1), but the cornerstone of this proposal will be the use of a placebo-controlled randomized surgical intervention (Fig. 2).

Figure 1
Figure 1
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Figure 2
Figure 2
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This proposed trial will be one of only a very few placebo-controlled surgical trials to have been undertaken in the United States in recent history.31,32 The relative absence of such trials is largely related to ethical constraints on the use of (nontherapeutic) placebos in (invasive/“risky”) surgical interventions (theoretically violating ethical risk-benefit considerations), but we believe the history of the field and other considerations supports and even mandates this approach.28,29,33,34 The rationale for this placebo-controlled surgical trial design is, more specifically, based on several tenets: (1) our previous clinical results with a minithoracotomy approach have demonstrated that it is safe, with no unanticipated serious adverse events and no deaths associated with the procedure, and is associated with only the expected risks of postoperative discomfort and recovery from surgery12,13; (2) these limited risks are balanced against the potential opportunity for this subject population, with about a 50% 5-year mortality risk to receive this theoretically beneficial intervention in a 3:1 randomization6; (3) true sham surgery (ie, skin incision) or use of saline controls would not allow testing of the central hypothesis—that the VEGF-All6A+ expression cassette is more efficacious than simple needle sticks to the heart and/or the adenovirus per se induce angiogenesis35; and (4) the potential participants are adults and, with proper informed consent process, are capable of properly evaluating and deciding on whether to take on this risk and avoid therapeutic misconception.33

Thus, together with a few other ongoing efforts in the field, there exists the possibility that the field of angiogenesis and cardiac gene therapy will overcome the obstacles of early failures in the clinical testing of this new field of intervention.

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CARDIAC STEM CELL THERAPIES

As opposed to angiogenic interventions that target ischemic but viable myocardium, cardiac stem cell interventions are designed to repopulate otherwise permanently scarred myocardium with contractile cells to restore and improve cardiac function.5,36,37 Given the ill-fated track record of clinical trials for angiogenic interventions for the treatment of heart disease, it could have been hoped that the advent of stem cell therapies to treat myocardial infarction would have avoided the pitfalls of ill-advised trial design. Unfortunately, this cellular cardiomyoplasty strategy has generated only limited demonstrated improvements in cardiac function in animal studies, and although generally well tolerated as assessed by safety measures in clinical trials, even these limited successes have generally not translated into significant improvements in efficacy metrics in clinical studies (Table 3).5,36,37 As further considered below, inappropriate trial strategies, perhaps based on “magical” thinking surrounding this new class of agents, again appear to lie at the core of these disappointing results.

Table 3
Table 3
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In our view, the disappointing efficacy outcomes of cellular cardiomyoplasty animal studies and clinical trials to date (involving stem cell administration into infarcted myocardium) are likely related, at a minimum, to the well-demonstrated failure of the great majority (>90%) of exogenously delivered cells to survive implantation. This deficiency is likely a result of peri-infarct inflammation/ischemia or inefficient cell delivery.48,49 Transfection of implants with survival factors, or with angiogenic transgenes that could generate a nutrient neovasculature, has therefore been proposed as a remedy.50,51 We and others have shown, however, that scar prevascularization with angiogenic mediators before cell implantation yields greater implant survival and functional efficacy than concomitant strategies do, likely on the basis of the weeks-long latent period between angiogenic mediator delivery and target tissue reperfusion.52,53 Likewise, we and others have shown functional benefits to the use of biomatrices in improving cell implantation efficiency and myocardial integration.54–57

Unfortunately, as with the angiogenic trials that preceded them, none of the significant number of stem cell clinical trials have been undertaken so far have incorporated either angiogenic pretreatment of the host myocardium, biomatrix platforms, or other enhanced stem cell delivery strategies. In contrast, a number of these studies have again incorporated intracoronary administration strategies, likely on the basis, again, of this approach facilitating incorporation of a placebo-controlled study design.5,36,37 As of yet, these clinical trial have likewise generally failed to take into consideration these cell delivery parameters or the bioactivity of these cells following myocardial incorporation (eg, electrical or contractile integration into the host syncytium) or even careful extrapolation from preclinical work as to the critical number of cells needed for generating efficacy. As with the angiogenic trials before them, it seems that the stem cell field may be hindered by an “irrational enthusiasm” surrounding this new biointervention.

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A NEXT GENERATION OF BIOINTERVENTION: IN SITU CARDIAC TRANSDIFFERENTIATION

New advances in stem cell technologies are today offering a third opportunity at effective biointerventions. These advances relate to the lack of an ideal candidate cardiomyocyte implant, in that source cells such as myoblasts and mesenchymal stem cells do not clearly differentiate adequately into contractile cardiomyocytes, and use of embryonic stem cells are limited by well-known ethical and procurement issues.

A breakthrough in this regard seemed to have come in the creation of induced pluripotent stem (iPS) cells from somatic cells such as fibroblasts and the demonstration by groups, including our own, that cardiomyocyte-like cells can be redifferentiated from iPS cells.58,59 Although redifferentiated iPS cells may well express an appropriate cardiomyocyte phenotype, recent concerns about iPS tumorogenicity and immunogenicity may, however, ultimately limit the clinical applicability of these cells.60

The more recent advent of “induced cardiomyocyte” (iCM) generation directly from somatic cells without passing through an iPS stage (using a trio of “cardio-differentiating” transcription factors [as now validated in our own laboratory]) offers the exciting new possibility of autologous cardiomyocyte implant production that bypasses potentially deleterious iPS staging.61,62 This capability would offer the even more intriguing possibility of converting scar fibroblasts into functional iCMs in situ, obviating the challenges of cell implant harvest, expansion, and delivery.63 On a cautionary note, even this technology will need thoughtful design of clinical trials. For example, iCM generation in situ in the infarct milieu would in our estimation need to incorporate angiogenic pretreatment to support the survival of transdifferentiated iCMs in an ischemic host environment.

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CONCLUSIONS

Taken together, we believe that these past two decades of clinical trials in angiogenic therapy and stem cell interventions largely reflect a naiveté that because these treatment trials involve relatively “exotic” approaches (gene therapy, stem cells), they are somehow special or different than other “drugs.” Clearly, the past 20 years of trial results has demonstrated that they are not. These trials must be designed with appropriate attention to drug delivery pharmacokinetics, postadministration bioactivity, and objective endpoint metrics. We hope to address some of these issues in our proposed placebo-controlled trial of angiogenic gene therapy using adenoviral-mediated transfer of VEGF, using what we believe to be an appropriate delivery strategy of a “drug” with apparent biologic efficacy, measured with objective endpoints (electrocardiogram changes on stress testing and computed tomography angiography). It will be important that subsequent trials in this new field be thoughtfully designed as well.

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Keywords:

Gene therapy; Stem cells; Angiogenesis; Heart failure; VEGF

Copyright © 2012 by the International Society for Minimally Invasive Cardiothoracic Surgery. Unauthorized reproduction of this article is prohibited.

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