In a new study published in Molecular Therapy, Dr. Sumit S Verma, Prof. Chandan K Sen and Dr. Kanhaiya Singh and colleagues have recognized that optimal VEGF therapy requires a favorable methylation status of its downstream signaling molecules in diabetic wounds. The rescue of one of the downstream signaling molecule PLCγ2 expression from hyperglycemia-dependent-hypermethylation stimulates tissue vascularization in diabetics during VEGF therapy.
Diabetic wounds are complicated by underlying peripheral vasculopathy. Reliance on vascular endothelial growth factor (VEGF) therapy to improve perfusion makes logical sense, yet clinical study outcomes on rescuing diabetic wound vascularization have yielded disappointing results. In this work, guided by single-cell RNA sequencing of human wound-edge, the efficacy of gene-targeted therapeutic demethylation intending to improve VEGF-mediated neovascularization was tested. To specifically demethylate endothelial PLCγ2 promoter during VEGF therapy, a CRISPR/dCas9-based demethylation cocktail was delivered to the ischemic wound-edge using tissue nanotransfection (TNT) technology. TNT-based delivery of plasmids to demethylate the PLCγ2 gene promoter activity led to significant improvements in VEGF therapy for cutaneous diabetic wounds, resulting in better perfusion and accelerated wound closure.
Full author list: Sumit S. Verma, Chandan K. Sen, Rajneesh Srivastava, Surya C. Gnyawali, Parul Katiyar, Ajay K. Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S. Abouhashem, Leila NW. Fehme, Sedat Kacar, Sujit K. Mohanty, Julie Faden-McCormack, Michael P. Murphy, Sashwati Roy, Jun Wan, Mervin C. Yoder, Kanhaiya Singh
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the U.S. Department of Defense, and the Commonwealth of Pennsylvania.
Read full article here: https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(25)00038-3