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Gene Therapy for Hypertension

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

We are developing antisense DNA in an adeno-associated viral vector (AAV) to integrate angiotensin II (AT1) receptor mRNA or angiotensinogen mRNA antisense in the genome of patients with hypertension. Initially, this will be tested in patients with a familial related angiotensinogen mutant that leads to overexpression of the renin-angiotensin system (RAS) and hypertension. If successful the gene therapy could be extended to a larger population of hypertensives and hypertension in pre-eclampsia. It is the goal of this research to provide, through gene therapy, an accurate, highly specific and effective treatment with few side effects that can overcome a major problem in hypertension treatment, namely the problem of compliance. A single injection, once a year or at longer intervals with effective control of hypertension, would dramatically reduce the need for daily intake of antihypertensive drugs, reducing costs and increasing effectiveness.

We have succeeded in reducing hypertension in spontaneously hypertensive rats (SHR) by the direct application of antisense oligonucleotides to angiotensinogen mRNA and angiotensin type-1 receptor mRNA. The next step is to develop a viral vector to deliver the antisense molecule to the nucleus for integration into the genome in peripheral tissues (e.g. liver) and to test its effectiveness on reducing hypertension. Our preliminary results have accomplished this using an AAV virosome vector in which we have cloned a full-length angiotensinogen and AT1 receptor DNA sequence inserted in the antisense direction. Injection of these vectors directly into liver, kidney and brain in vivo, has so far shown the feasibility of gene transfer by immunocytochemical demonstration of the viral rep gene expression in cells close to the site of injection. In SHR, the antisense to the AT1 receptor in a single injection produced a decrease in blood pressure that lasted for 7-9 days. Therefore, we anticipate that gene therapy with an integrative antisense DNA to AT1-R will produce prolonged decreases in blood pressure due to reduced numbers of AT1 receptors with only a single transfection. Although we have thus far tested only virosomes (liposomes containing Sendai viral coat proteins) we are also preparing to test contentional AAV recombinant virus as delivery vectors in collaboration with the Vector Core staff of the Gene Therapy Center. For this purpose we have developed an AAV with cDNA to angiotensinogen mRNA and AT1 receptor mRNA inserted in the antisense direction and under the control of a CMV promoter. We anticipate that within the next five years we will be prepared for gene therapy protocols in hypertensive patients on the GCRC.

Reference

  1. Gyurko R, Wielbo D, Phillips MI. Antisense inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. Reg Peptides 94:167-174, 1993.
  2. Phillips M. Prolonged reduction of high blood pressure with an in vivo, nonpathogenic adeno-associated viral vector delivery of AT-R mRNA antisense hypertension. 29:374-380, 1997