Enhanced mRNA Gene Therapy for Critical Limb Ischemia

Jorge Pincay ‘20

Screen Shot 2019-10-15 at 8.28.46 AM
Figure 1. Synthetic mRNA can be chemically modified to express VEGF in targeted areas.

Critical limb ischemia (CLI) is a cardiovascular condition characterized by severely narrowed arteries resulting from the buildup of plaque. This narrowing of the arteries  significantly reduces blood flow to the hands, feet, and legs and may lead to amputation of the affected limbs. Most patients suffering from CLI need to undergo some form of a revascularization procedure in order to combat this disease. However, almost 50% of CLI patients are not suitable for such procedures. As a result, mRNA gene therapy has begun to receive more attention as a means of inducing angiogenesis, or the growth of new blood vessels, in these ischemic patients. 

These mRNA molecules are chemically modified to code for Vascular Endothelial Growth Factor (VEGF), a growth factor for endothelial cells that stimulates angiogenesis. The limitations to this form of therapy lie within the methods of delivery. Direct injection of these modified RNAs (modRNAs)has proven to be somewhat effective, but it has been hypothesized that through this process a portion of the modRNA transcripts are lost due to degradation by RNases or insufficient uptake of these modRNAs by the cell. These obstacles have given rise to the need for more effective methods for the delivery of these modRNAs. 

Recently, a team of researchers from Shanghai Jiao Tong University and Karolinska Institute has shown that cell-mediated delivery of these modified RNAs using fibroblasts as modVEGF carriers can promote more potent angiogenic effects compared to other methods of delivery, such as lipoplex-mediated delivery, which uses a complex of DNA and liposomes as a modVEGF carrier, and direct injection of modVEGF. Mouse models were used to compare the effectiveness of these methods. Mice that were subcutaneously injected with fibroblasts containing modVEGF  had larger blood vessel formation, increased VEGF expression, and greater capillary density compared to mice that received the lipoplex modVEGF injection and mice that received the direct modVEGF injection. In addition, all vital organs remained intact after performing a cell-mediated delivery of modVEGF in mice, which provides evidence for little to no toxicity risk. 

The findings within this study have proven that cell-mediated delivery of modVEGF may be a feasible treatment option for CLI patients who are ineligible for revascularization procedures. Furthermore, this study has demonstrated that the combination of mRNA and cell therapies may have the potential to revolutionize the treatment of vascular disease.  

 

References:

  1. Z. Yu, et al., Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia. Journal of Controlled Release 310, 103-114 (2019). Doi:10.1016/j.jconrel.2019.08.014.
  2. Image retrieved from: https://www.news-medical.net/life-sciences/mRNA-Display-Applications-in-Research.aspx

 

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