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L4. Cell Based Gene Therapy to Reestablish Stem Cell Homing Improves Cardiac Function In Ischemic Cardiomyopathy
Indu Deglurkar, Zoran Popovic, Matthew Kiedrowski, Patrick Mccarthy, Marc S Penn; Cleveland, OH

Objective: Reestablishing chronic expression of the homing factor SDF-1 causes stem cell homing to the injured myocardial and improves cardiac function. Unfortunately, the chronic expression of SDF-1 could theorectically cause untoward effects such as hemangioma formation. We wanted to determine if transient SDF-1 expression enabled by cell based gene therapy using adenovirally infected skeletal myoblasts (SKMB) is sufficient to recover cardiac function.
Methods: A third generation adenovirus encoding the human SDF-1 gene driven by a CMV promoter was generated. SKMB were infected 18 h before SKMB transplantation with AdSDF-1-myc (Study Group 1) or AdGFP (Study Group 2). Anterior myocardial infarction was induced in 31 male Lewis rats by direct ligation of the proximal left anterior descending artery. After 6 weeks, redo-sternotomy was performed on 23 rats. Study group I (n=15) received in the peri-infarct zone one million autologous SKMB transfected with hSDF-1 in 5 divided doses. Study Group II (controls n=8) received one million SKMB transfected with GFP. Echocardiograms were performed post-infarction and 4 weeks after cell transplantation. In separate animals, to determine the arrhythmogenic risk and to further assess the myocardial regenerative capacity of this strategy, surface electrical mapping is being performed.
Results: Shortening fraction in Study Group I, from 9.8%±2.8% to 14.7%±3.3% (P=.005), but changed from only 8.0%±5.2% to 9.5%±3.1% (P=0.005) in Control Group II at 4 weeks. Immunohistochemistry in the infarct zone revealed significantly greater vascular density in those animals that received SDF-1 expressing SKMB. Localization of SDF-1 through immunostaining for myc suggests that SDF-1 is taken up by cardiac myocytes in the infarct border zone. Surface mapping will determine if this strategy leads to the development of increased arrhythmic potential and/or alters the electrical conduction across the infarct zone.
Conclusion: The transient expression of the stem cell homing SDF-1 through the transplantation of genetically modified autologous SKMB at a time remote from myocardial infarction is sufficient to improve cardiac function, partly through the recruitment of new blood vessels, and partly through anti-apoptotic effects of SDF-1 uptake by cardiac myocytes in the infarct border zone. These data suggest a novel therapeutic strategy to improve left ventricular function without the need to introduce cells that are genetically altered permanently.

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