Novel Strategies Advance Cell Therapy for Cardiomyopathy
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NEW YORK, NY—Two early-stage trials of innovative approaches to cell therapy have proved safe and appear to aid in reversing chronic cardiomyopathy. The data were presented January 26, 2012, at the Seventh International Conference on Cell Therapy for Cardiovascular Disease.
Both studies addressed a major impediment to cell therapy for nonacute heart failure—impaired homing of cardiac stem cells. They did this by augmenting the availability of stromal cell derived factor 1 (SDF-1), which plays a key role in natural cardiac repair by attracting and retaining therapeutic bone marrow mononuclear cells and promoting neovascularization.
Riding the Shock Waves
The first study drew on preclinical evidence suggesting that applying extracorporeal pulses of electrical energy, or ‘shock waves’ (Dornier Med Tech Systems, Wessling, Germany), to ventricular tissue stimulates release of SDF-1.
Andreas M. Zeiher, MD, of Goethe University, Frankfurt (Frankfurt, Germany), presented results of the phase 1/2 CELLWAVE trial, which were first reported at the American Heart Association Scientific Sessions in November 2011.
German researchers initially randomized 103 patients with chronic stable heart failure an average of 6 years post MI in a 2:2:1 ratio to low-dose shock waves (0.014 J/mm2; n = 42), high-dose shock waves (0.051 J/mm2; n = 40), or a sham procedure (n = 21). All therapies were targeted to the left ventricular anterior wall. The following day, after bone marrow aspiration, patients in the 2 shock wave-treated groups were randomized to intracoronary administration of autologous bone marrow cells (low-dose shock wave n = 22; high-dose shock wave n = 21) or placebo; the sham group also received bone marrow therapy.
Shock wave pretreatment proved generally safe, with 1 patient in the high-dose group showing a troponin elevation, while in the low-dose group 1 patient experienced ventricular tachycardia requiring an ICD and another suffered a stroke.
Improvements in Cardiac Function, Symptoms
Among all shock wave-pretreated patients, the absolute change in LVEF by 4 months, the primary endpoint, was almost threefold greater in the bone marrow-treated arm than the placebo arm (P = 0.01). Moreover, in patients with a baseline LVEF less than 40%, there was a dose-response effect of shock wave pretreatment, with a relative 17% increase in LVEF of the high dose over the low dose (P = 0.04 for trend). The proportion of patients in New York Heart Association (NYHA) classes I and II increased from baseline in the bone marrow-treated arms of the low- and high-dose shock wave groups (P = 0.05 and P = 0.03, respectively), while there was no change in the placebo arms of those groups (P = 0.82 and P = 0.79, respectively).
Clinical improvement was corroborated by changes in NT-proBNP levels, which were significantly reduced in the bone marrow-treated shock wave arm (P = 0.04) but not the placebo-treated shock wave arm (P = 0.18) or the bone marrow-treated group that did not receive shock waves (P = 0.64).
Three-year follow-up, available for 77% of the study population, found fewer adverse events, including cardiac death, hospitalization for heart failure, revascularization, and ventricular tachycardia, in shock wave-pretreated patients who received bone marrow therapy compared with those who received placebo.
According to Dr. Zeiher, MRI-confirmed increased infarct wall thickening (P for trend = 0.01) and decreased infarct size (P for trend = 0.002) in patients who received both shock waves and cell therapy points to a probable mechanism behind clinical improvements.
Dr. Zeiher concluded, “Given the excellent safety profile and the observed effect on long-term major adverse cardiac events, shock wave-facilitated intracoronary administration of autologous bone marrow-derived cells holds great promise to beneficially [affect] clinical outcome in patients with chronic post-infarction heart failure.”
A DNA Boost to Repair
Meanwhile, Marc S. Penn, MD, PhD, of Northeast Ohio Medical University (Rootstown, OH), reported on a molecular strategy to promote SDF-1 availability. After a traumatic injury such as an MI, the heart releases SDF-1, but about a week after the injury, SDF-1 expression—and thus the homing signal for autologous stem cells—fades.
To assess the safety of delivery of a nonviral DNA vector encoding SDF-1 (JVS-100; Juventas Therapeutics; Cleveland, OH), investigators at multiple centers enrolled 17 patients with class III heart failure and LVEF of less than 40% who were an average of 7.3 years post MI. The subjects received injections of SDF-1 plasmid at doses of 5 mg (n = 4), 15 mg (n = 6), or 30 mg (n = 7).
All doses were well tolerated, and at 30 days no major adverse cardiac events related to the drug were reported.
At 4 months, patients in the postulated therapeutic range (15 mg or 30 mg) showed a clinically and statistically significant median improvement of 36 meters in the 6-minute walk distance test (P = 0.001) and a significant increase of 22 points in the Minnesota Living with Heart Failure Questionnaire (P = 0.029). Moreover, almost half of patients improved a full NYHA class while none worsened in symptom class. The improvements were maintained at 12 months, although 6-minute walk distance declined at this point.
In addition, cardiac function stabilized, with dose-dependent trends toward improvement in LVEF (7% absolute increase between 5 mg and 15 mg or 30 mg doses; P < 0.07) and left ventricular end systolic volume.
Dr. Penn concluded that “re-establishment of SDF-1 expression late in acutely or chronically injured tissue leads to improvement in clinical status.” A randomized phase 2 trial involving 90 patients receiving either 15 mg or 30 mg doses of SDF-1 is scheduled to begin in the summer of 2012, he added.
Sources:1. Penn MS. SDF-1 for heart failure. Presented at: Seventh International Conference on Cell Therapy for Cardiovascular Diseases; January 26, 2012; New York, NY.
2. Zeiher AM. Cardiac extracorporeal shock wave application to enhance the efficiency of intracoronary cell therapy in chronic heart failure. Results of the randomized, double-blind, placebo-controlled CELLWAVE trial. Presented at: Seventh International Conference on Cell Therapy for Cardiovascular Diseases; January 26, 2012; New York, NY.
- Dr. Penn reports being a founder of and holding equity in Cleveland Heart Lab, Juventas Therapeutics, and SironRx Therapeutics.
Novel Strategies Advance Cell Therapy for Cardiomyopathy
- Dr. Zeiher reports serving as a consultant to and advisory board member for t2cure.