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Gene Therapy for Arterial Restenosis

M. Ian Phillips, Ph.D., D.Sc.

Angiotensin II (Ang II) has been implicated as a growth factor in vascular smooth muscle (VSM) and, at least in animal models, Ang II causes the excessive growth of VSM which leads to restenosis in blood vessels after balloon catheterization. The proliferation of vascular muscle after balloon angioplasty causing blood vessels to close again within weeks or months is a serious clinical problem. We propose to approach it by developing antisense DNA to angiotensin II (AT1) receptor mRNA delivered in an adeno-associated virus (AAV) during the balloon angioplasty. We hypothesize that genetic intervention in the blood vessel, after balloon injury, can produce genomic antisense DNA to components of the renin-angiotensin system which will decrease the growth stimulating effects of Ang II and allow full recovery without restenosis.

We have successfully used the rat model for balloon angioplasty and vascular smooth muscle hypertrophy. We have used FITC labelled antisense to AT1 receptors to show that the antisense is taken up into VSM and retained intact in the cells. The vector delivered antisense DNA is taken up by the cells and integrated into the chromosomes. It can then be transcribed and translated to produce antisense mRNA which hybridizes to the AT1-R mRNA and prevents translation. The AAV vector will have a reporter gene for use with atherectomy catheters in humans. The tissue removed by atherectomy will be analyzed for presence of the reporter gene to ensure that the vector had been delivered into the tissue surrounding the area of angioplasty. This approach was tested in rats and will be retested in pigs because of the close similarity between pig vascular biology and human vascular biology. Since the vector is integrated in the chromosome and becomes unnecessary past the critical period for restenosis, the possibility of inserting a “suicide” gene which can be triggered (e.g. by ganciclovir) will be considered. Patients recruited to the GCRC will be cardiology patients, supervised by the Division of Cardiology. Patients will be followed intensively for three months for signs of changes in coronary blood flow and tissue perfusion and thereafter for life, using the resources of the OCI.

References

  1. Meng H, Wielbo D, Gyurko R, Phillips MI. Antisense oligonucleotide to AT1 receptor mRNA inhibits central angiotensin induced thirst and vasopressin. Reg Peptides 54:543-551, 1994.
  2. Phillips MI, Wielbo D, Gyurko R. Antisense inhibition of hypertension: A new strategy for renin-angiotensin candidate genes. Kid Intern 46:1554-1566, 1994.