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Gene therapy for heart transplantation-associated coronary arteriosclerosis
M Isobe1, J Suzuki, R Morishita
1Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan. isobemi.med3@med.tmd.ac.jp
Abstract:
Cardiac allograft arteriosclerosis, which limits the long-term survival of recipients, cannot be prevented by conventional therapies. The arteriopathy is characterized by diffuse intimal thickening made up of proliferative smooth muscle cells. To test the hypothesis that cell cycle-regulatory genes play crucial roles in the development of this arteriopathy in vivo gene therapy targeting cell division cycle (cdc) 2 kinase was attempted in murine cardiac allografts using hemagglutinating virus of Japan (HVJ)-liposome method. Antisense cdc 2 kinase oligodeoxynucleotide (ODN) was transfected into the allografts by intraluminal injection during the operation and the allografts were harvested at 4 weeks after transplantation. Coronary intimal thickening had developed in sense ODN-treated allografts and ICAM-1 and VCAM-1 were enhanced in these arteries. PDGF mRNA was also detected. Antisense cdc 2 kinase ODN inhibited intimal hyperplasia. These data indicate that antisense cdc 2 kinase modulates gene expression and inhibits smooth muscle cell proliferation of graft arteries.
Insights
Gene therapy targeting cell division cycle (cdc) 2 kinase using antisense oligodeoxynucleotide (ODN) effectively inhibited cardiac allograft arteriosclerosis by reducing smooth muscle cell proliferation in graft arteries.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Immunology
Background:
- Cardiac allograft arteriosclerosis is a major cause of long-term graft failure, characterized by intimal thickening due to smooth muscle cell proliferation.
- Conventional therapies are ineffective in preventing this post-transplant arteriopathy.
- Cell cycle-regulatory genes are implicated in the development of vascular diseases.
Purpose of the Study:
- To investigate the role of cell cycle-regulatory genes in cardiac allograft arteriosclerosis.
- To evaluate the efficacy of in vivo gene therapy targeting cell division cycle (cdc) 2 kinase in preventing this condition.
Main Methods:
- Murine cardiac allografts were used to model cardiac allograft arteriosclerosis.
- In vivo gene therapy was performed using the hemagglutinating virus of Japan (HVJ)-liposome method to deliver antisense cdc 2 kinase oligodeoxynucleotide (ODN).
- Antisense ODN was administered via intraluminal injection during surgery, with allografts harvested at 4 weeks post-transplantation.
Main Results:
- Control allografts (sense ODN-treated) exhibited significant coronary intimal thickening, enhanced ICAM-1 and VCAM-1 expression, and detected PDGF mRNA.
- Antisense cdc 2 kinase ODN treatment significantly inhibited intimal hyperplasia in the graft arteries.
- The treatment modulated gene expression and suppressed smooth muscle cell proliferation within the graft arteries.
Conclusions:
- Targeting cdc 2 kinase with antisense ODN is a promising therapeutic strategy for preventing cardiac allograft arteriosclerosis.
- This gene therapy approach effectively inhibits smooth muscle cell proliferation and reduces intimal thickening in cardiac allografts.
- The findings highlight the critical role of cdc 2 kinase in the pathogenesis of allograft arteriopathy.