Myocardial Delivery of SDF1 in Patients with Ischemic Heart Disease: Safe & Promising

Heart Failure (HF) is a leading cause of mortality and morbidity in the US and its prevalence continues to increase especially as the population ages¹. A significant cause of heart failure is ischemic heart disease¹. Myocardial infarction and chronic ischemic disease can lead to the loss of a substantial number of cardiac myocytes thus justifying attempts to design an efficacious regenerative therapeutic strategy^{2, 3}. Initial studies have documented the safety and feasibility of administrating stem or progenitor cells to restore the lost myocardium. Recently, intracoronary infusion of autologous c-kit+ cardiac stem cells in a Phase 1 trial resulted in significant clinical improvements in patients with ischemic cardiomyopathy. ^{4, 5}

The recent demonstration of adult human cardiac renewal and the progressive and extensive characterization of progenitor cells in the heart have revealed that the heart has regenerative potential². Even though the heart has regenerative capacity, it is clear that it is inadequate to replace the massive loss of cardiomyocytes in the setting of myocardial infarction(s) ^{2, 3}. There is mounting evidence that following ischemic insults, a number of factors are activated that lead to the recruitment of progenitor cells to the site of injury^6-8. These results provide hope for the development of therapeutic strategies to augment the limited regenerative process for the failing heart. In this issue, Penn and colleagues report preliminary results on the safety and feasibility of injecting stromal cell-derived factor-1 (SDF-1) in the myocardium of patients with ischemic heart disease. SDF-1, also known as CXCL12, is a constitutively expressed and inducible chemokine that is transiently up-regulated in response to tissue injury. Pre-clinical studies indicate that SDF-1 increases stem cell homing by stimulating the CXCR4 receptor in these cells. The CXCL12-CXCR4 axis has been shown to have anti-apoptotic effects and induces angiogenesis and inhibits fibrosis. During myocardial infarction, the increased expression of SDF-1 has been thought to act as a cellular signal to attract potentially beneficial stem cells to repair, and possibly regenerate, damaged myocardium. SDF-1 expression is increased in the myocardium but only for the seven days following an infarction. In this study, the investigators capitalize on the relationship between SDF-1 and stem cell homing and propose to prolong SDF-1 expression with the goal of promoting endogenous cardiac repair.

In this Phase I open-label dose-escalation study patients with ischemic cardiomyopathy received one of three doses of SDF-1: 5, 15 or 30 mg via endomyocardial injection. The patients were followed for 12 months with assessment of several outcomes including major adverse cardiac events, non-invasive measurement of left ventricular function and volumes, changes in BNP (Brain Natriuretic Factor), quality of life and myocardial perfusion as measured by SPECT imaging. Seventeen patients were enrolled and fifteen completed the 12-month follow-up. Overall, endomyocardial administration of SDF-1 was found to be feasible and safe. Although this phase I trial was designed primarily to assess the safety of the approach in humans, the authors report several efficacy endpoints. The limited number of patients precludes drawing firm conclusions on the beneficial effect of SDF-1 administration in this patient population but a couple of parameters merit attention. The left ventricular function and volumes were stable over the 12-month follow-up without clear differences between the three treatment groups.

Despite this, patients receiving the highest doses (15 and 30 mg) were found to have an improvement in their clinical status including quality of life, 6-minute walk test and NYHA (New York Heart Association) class.

The investigators used plasmid DNA to deliver SDF-1 to the myocardium. This delivery method induces short-term expression of SDF1 which is a reasonable choice based on the biology of this agent ⁹. The efficiency of plasmid based DNA delivery is quite low but is relatively safe and has low immunogenicity ⁹. In addition, plasmid DNA does not have packaging limitations that restricts the transgene size ¹⁰. In contrast, recombinant adenoviral vectors induce higher expression with a short-time course, however the inflammatory response they cause would not be acceptable in this patient population ¹⁰. Recombinant adeno-associated vectors or lentiviruses, other viral vectors that are commonly used in cardiovascular applications, would induce long-term expression of SDF-1, which may cause untoward effects especially as the transgene would be expressed in other tissues ¹⁰.

The investigators used a direct intra-myocardial delivery route to express SDF-1 in peri-infarcts areas. Fifteen 1ml injections in the peri-infarct areas identified by cardiac echocardiography were performed in the patients. The primary advantage of this method is that plasmid delivery bypasses the endothelial barrier. This results in a high local concentration at the injection site ¹⁰. In addition, by avoiding exposure to the blood, deactivation of the vectors by circulating DNAses can be prevented. There is also minimal exposure of the plasmid to off-target organs, although local administration cannot completely avoid some systemic vector distribution. Despite using specialized infusion catheters with helical needles, the retention of plasmid or vector delivered by this method is quite low and decreases the efficiency of local expression.

Different experimental models have shown that SDF-1 regulates adult vasculogenesis and neo-vascularization ^{11, 12}. Interestingly, the authors report a significant improvement in myocardial perfusion (assessed by SPECT imaging) in the two groups receiving the highest dose (15mg and 30mg) as compared to the low-dose (5 mg) group. The regional changes in myocardial perfusion as well as myocardial viability were not reported but would help in understanding the angiogenesis-dependent and –independent effects of SDF-1 in the failing heart.

There are specific issues with the design of the clinical trial that tempers enthusiasm for the positive data reported. As an open-label study without a placebo controlled arm, it is difficult to place the clinical improvements in any context. At the 4-month follow-up, three out of the seven parameters measured trended towards a worsening state. NT-proBNP along with ESV trended upwards at the 12 month follow-up for the low and mid dose groups. The data do not suggest any concordance that would reduce false-positive rates. Combining the mid and high dose groups to gain statistical significance is also questionable; in fact this statistical maneuver was not pre-defined in the clinical design. Finally as is typical for a small phase 1 study, there were baseline imbalances among groups that could have resulted in meaningful differences.

Despite these shortcomings, this clinical trial shows the feasibility of this strategy to enhance recruitment of progenitor cells in patients with ischemic cardiomyopathy. Further clinical studies are eagerly anticipated.