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EDITORIAL |
Singapore
Skeletal myoblast (SkM) transplantation has been extensively investigated as a potential treatment modality in cardiovascular therapeutics, and the functional benefits of this procedure have been validated in animal models and clinical studies.1 Preclinical studies have well demonstrated that SkM is a safe and efficient cell type for cardiac repair. It improves systolic and diastolic function, increases myocardial wall thickness, and delimits the ventricular remodeling process. Skeletal myoblasts are as effective as neonatal cardiomyocytes and bone marrow-derived stem cells for cardiac repair.2–4 Since Menasche and colleagues5 reported the first patient to receive autologous SkM transplantation as an adjunct to coronary artery bypass grafting, more than 200 patients have undergone SkM transplantation. Except for transient ventricular tachycardia or arrhythmia observed in some patients, SkM transplantation has been well tolerated in general, and has not been associated with adverse effects. In most patients, there was improvement in New York Heart Association functional class, increased wall thickness, restored contractility, and reversal of the left ventricular remodeling process.
Because SkM-mediated gene delivery is safer and a more efficient and convenient alternative to conventional protein replacement therapy, SkMs have been used as carriers of angiogenic genes for angiomyogenesis. Skeletal myoblast-mediated angiogenic gene transfer can simultaneously introduce new myogenic cells and induce neovascularization in the infarcted heart. The beneficial effects of angiogenic gene therapy are derived from enhanced neovascularization and improved regional perfusion. Neovascularization involves formation of new capillaries via endothelial cell proliferation triggered by angiogenic ligands and their receptors, and homing of angiogenic progenitor cells.6 The angiogenic protein is expected to enhance the survival of transplanted cells in the early stage after cell transplantation, and prevention of the direct exposure to viral vectors avoids the immunological problem. We have demonstrated that transplantation of SkMs carrying angiogenic genes is a superior strategy to the use of either SkM or angiogenic gene therapy alone. The transient expression of angiogenic protein efficiently induced neovascularization and improved regional blood perfusion with better functional recovery of the injured heart.7–9
Indeed, the angiogenic and myogenic potential of genetically engineered SkMs makes them near-ideal cells for transplantation therapy. However, several factors need to be optimized before translation into clinical use. Firstly, the success of SkM transplantation is compromised by massive early cell death and poor donor cell survival after injection.10 Most donor SkMs perish within 48 hours after implantation. This unwanted happening in terms of cell survival is critical and not only drastically reduces the number of functioning donor cells but also initiates an inflammatory response triggered by the dead SkMs. Strategies to prevent SkM death in the early stage after transplantation should be developed. Our experience with a xenotransplantation model suggests that transient immunosuppression (cyclosporine 5 mg·kg–1) could improve the survival rate of cells in the early stage after transplantation.11 Secondly, the inability of the donor SkMs to electrophysiologically couple with the host cardiomyocytes causes electrical abnormalities, such as ventricular tachycardia or arrhythmia. This major deficiency of SkMs has been compensated for by genetic modification of the SkMs to over-express connexin-43.12
The choice of angiogenic genes for delivery via SkM transplantation remains an important factor. Most of the therapeutic angiogenic gene studies only explored single-gene delivery for neovascularization, despite the fact that the angiogenic cascade involves multiple growth factors and cells. Hence, simultaneous administration of multiple angiogenic factors may be an ideal way to mimic the natural course of the angiogenic process. For that matter, a strategy to achieve optimum transgene delivery into SkMs is imperative. Although viral vectors have demonstrated high transduction efficiency, the immunogenic nature and oncogenic potential of viral vectors severely hamper their clinical application. In the light of these concerns, non-viral gene delivery should be used. The use of polymer-based nanoparticles confers several advantages.13 Polyethylenimine has strong DNA compaction capacity with an intrinsic endosomolytic activity, and has been considered the gold standard to compare with other polymers. In a recently concluded study, we demonstrated the feasibility and efficacy of polyethylenimine-based nanoparticles for transfection of human SkMs with plasmid encoding for human VEGF165.14
Most of the studies to date have reported the effect of short-term and transient over-expression of angiogenic growth factors. The usefulness of integrating angiogenic genes for longer-term low-level expression for therapeutic myocardial angiogenesis remains unclear. High-level long-lasting expression of potent angiogenic growth factors may cause harmful side effects such as induction of angioma formation.15,16 Thus a regulatable gene expression system should be used. The expression of angiogenic genes will be subjected to control by exogenous switches, such as hypoxia, which may signal an on or off of the gene expression.
REFERENCES
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