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.
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.
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.
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.
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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