Researchers have established a novel gene therapy strategy which is an excellent substitute for the current expensive and uncontrollable Vascular endothelial growth factor (VEGF) gene delivery system.
The discovery of the hyperbranched poly(amidoamine) (hPAMAM) nanoparticle based hypoxia regulated vascular endothelial growth factor (HRE-VEGF) gene therapy strategy, by Dr Changfa Guo, Professor Chunsheng Wang and their co-investigators from Zhongshan hospital Fudan University, Shanghai, China, provides an economical, feasible and biocompatible gene therapy strategy for cardiac repair.
Transplantation of VEGF gene manipulated mesenchymal stem cells (MSCs) has been proposed as a promising therapeutic method for cardiac repair after myocardium infarction.
However, the gene delivery system, including the VEGF gene and delivery vehicle, needs to be optimized. On one hand, long-term and uncontrollable VEGF over-expression in vivo has been observed to lead to hemangioma formation instead of functional vessels in animal models.
On the other hand, though non-viral gene vector can circumvent the limitations of virus, drawbacks of the current non-viral vectors, such as complex synthesis procedure, limited transfection efficiency and high cytotoxicity, still needs to be overcome.
“Hypoxia response elements were inserted into the promoter region of VEGF gene to form HRE-VEGF, which provided a safer alternative to the conventionally available VEGF gene,” co-investigators, Kai Zhu and Hao Lai, said.
“The HRE-VEGF up-regulates gene expression under hypoxic conditions caused by ischemic myocardium and turns it off under normoxia condition when the regional oxygen supply is adequate,” they said.
The hPAMAM nanoparticles, which exhibit high gene transfection efficiency and low cytotoxicity during the gene delivery process, can be synthesized by a simpler and more economical one-step/pot polymerization technique.
“Using the hPAMAM based gene delivery approach, our published and unpublished results explicitly demonstrated that it was an economical, effective and biocompatible gene delivery vehicle,” they said.
Guo concluded by saying that “myocardium infarction improved the myocardial VEGF level”.
“Treatment with hPAMAM-HRE-VEGF transfected MSCs after myocardium infarction improved the myocardial VEGF level, which improved graft MSC survival, increased neovascularization and ultimately improved heart function. And this novel VEGF gene delivery system may have clinical relevance for tissue repair in other ischemic diseases,” Guo added.
The study has been published in Experimental Biology and Medicine.