Improved Homing of Cardiac Stem Cells Shows Promise for Cardiomyopathy

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A novel stem cell-based method of tissue repair via gene therapy has emerged as a potential treatment option for improving heart failure symptoms in patients with ischemic cardiomyopathy, according to a study published online February 21, 2013, ahead of print in Circulation Research.

Initial data were presented at the Seventh International Conference on Cell Therapy for Cardiovascular Disease in January 2012 in New York, NY

Addressing a major impediment to cell therapy for nonacute heart failure—impaired homing of cardiac stem cells—Marc S. Penn, MD, PhD, of Northeast Ohio Medical University (Akron, OH), and colleagues augmented 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. More specifically, the study used JVS-100, a DNA plasmid encoding human SDF-1.

The researchers enrolled 17 patients with ischemic cardiomyopathy due to prior MI on stable medical therapy. The patients, who all had LVEF ≤ 40% and were classified as NYHA functional class III, were given either 5 mg (n = 4), 15 mg (n = 6), or 30 mg (n = 7) of JVS-100 (Juventas Therapeutics, Cleveland, OH) via endomyocardial injections into peri-infarcted zones (BioCardia Helical Infusion Catheter, BioCardia, San Carlos, CA).

Higher Doses Most Effective

Following dosing, cardiac enzymes were measured at 6, 12, and 18 hours postinjection. In all patients, there was a slight increase in troponin I levels at 6 hours (median 1.7 ng/mL) that decreased substantially (median 0.7 ng/ml) at 18 hours.

At 1 month, the primary safety outcome was met with only 3 MACE events reported. At 12 months, 26 significant adverse events occurred in 8 patients, although none were linked to the study drug. Two patients died over the study period, but neither death was related to the study drug, procedure, or device.

At 4 months, each dose cohort demonstrated improvements in 6-minute walk distance test, quality of life, and NYHA class (primary efficacy endpoints). The 15-mg and 30-mg groups each saw substantial increases in 6-minute walk distance (median change 41 m and 31 m, respectively), which became statistically significant when the groups were combined (P < 0.002). Improvements over baseline were sustained in the 30-mg and combined groups through 12 months of follow-up.

Quality of life—measured using the Minnesota Living with Heart Failure Questionnaire—improved by 16 and 24 points in the 15-mg and 30-mg groups, respectively, at 4 months compared with baseline. Also, patients in the combined 15-mg and 30-mg dose group had 10- and 19.5-point greater improvements compared with the 5-mg group at 4 and 12 months, respectively. At both 4 (P < 0.05) and 12 months (P < 0.01), patients in the combined medium- and high-dosing group exhibited significant gains in quality of life.

Echocardiographic assessment showed general stabilization of cardiac function at 4 and 12 months. There were small dose-dependent decreases in LVEF and increases in left end systolic volume, but none were significant.

While a higher percentage of patients improved at least 1 NYHA class in the 15-mg (40%) and 30-mg (50%) groups compared with the 5-mg group (25%), no patient experienced a worsening of NYHA class at 4 months.

A ‘Boost’ to Stem Cell Therapy

In a telephone interview with TCTMD, Dr. Penn said his team “always took a different approach to the stem cell space, making the argument that stem cell-based repair is a natural process but clinically inefficient, not because we lack stem cells but because we lack the process.”

He likened the novel technique to treating a cold with drugs. “We don’t give more immune cells, we give something to boost the system,” Dr. Penn said. “This may suggest that we can boost our repair system through stimulation with drugs and not have to pull the cells out and stick them back where we want them.”

The study provided “enough of a proof-of-concept” to continue with additional research, Dr. Penn said, adding that that larger placebo-controlled, randomized trials are currently enrolling, though the 5-mg dose has been eliminated.

‘Preliminary’ Yet ‘Exciting’

In an accompanying editorial, Roger J. Hajjar, MD, and Jean-Sebastien Hulot, MD, PhD, of Icahn School of Medicine at Mount Sinai (New York, NY), say 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.”

The editorial notes specific issues with the design of the study that “[temper] enthusiasm for the positive data reported.” First, the lack of a placebo-controlled arm makes it “difficult to place the clinical improvements in any context,” they write. Also “at the 4-month follow-up, 3 out of the 7 parameters measured trended towards a worsening state. . . . 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.”

Dr. Penn argued that the combined analysis was preplanned, but “more importantly, there actually was concordance of results. The highest-dose cohort had improvements,” he said. “Patients who tended to respond tended to respond across the board. For us that was very reassuring. I think a lot of heart failure trials are showing that you don’t have to improve heart function to improve clinical status.”

Though the results are “very preliminary,” they are still “very exciting,” according to Joshua M. Hare, MD, of the University of Miami Miller School of Medicine (Miami, FL). He told TCTMD in a telephone interview that the study represents “an important contribution largely because it’s a unique strategy” involving gene therapy for heart failure

Sources:

  1. Penn MS, Mendelsohn FO, Schaer GL, et al. An open label dose escalation study to evaluate the safety of administration of non-viral SDF-1 plasmid to treat symptomatic ischemic heart failure. Circ Res. 2013;Epub ahead of print.
  2. Hajjar RJ, Hulot J-S. Myocardial delivery of SDF1 in patients with ischemic heart disease: Safe and promising. Circ Res. 2013;Epub ahead of print.

 

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Improved Homing of Cardiac Stem Cells Shows Promise for Cardiomyopathy

A novel stem cell based method of tissue repair via gene therapy has emerged as a potential treatment option for improving heart failure symptoms in patients with ischemic cardiomyopathy, according to a study published online February 21, 2013, ahead of
Disclosures
  • The study was funded by Juventas Therapeutics.
  • Dr. Penn reports receiving royalties from, holding equity in, and serving as a paid consultant to Juventas Therapeutics.
  • There is no statement regarding conflicts of interest for Dr. Hajjar.
  • Dr. Hare reports receiving research support from BioCardia.

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