(Hypertension. 1997;29:374.)
© 1997 American Heart Association, Inc.
State-of-the-Art-Lecture |
Prolonged Reduction of High Blood Pressure With an In Vivo, Nonpathogenic, Adeno-Associated Viral Vector Delivery of AT1-R mRNA Antisense
From the Department of Physiology, College of Medicine, University of Florida, Gainesville, Fla, and Harvard Medical School (P.W.), Boston, Mass.
Correspondence to Dr M.I. Phillips, Department of Physiology, College of Medicine, University of Florida, Gainesville, FL 32610. E-mail MIP{at}phys.med.ufl.edu
To produce a prolonged decrease in blood pressure, we have developed a nonpathogenic adeno-associated viral vector (AAV) with the antisense DNA for AT1-R. AAV has many advantages over other viral vectors. AAV does not stimulate inflammation or immune reaction. AAV enters nondividing cells and does not replicate. Therefore, it is an appropriate choice for gene therapy. Recombinant AAV was prepared with a cassette containing a cytomegalovirus promoter and the cDNA for the AT1 receptor inserted in the antisense direction. The cassette was packaged in the virion. Stable transfection of NG108-15 cells with the pAAV-AS (plasmid AAV) antisense to AT1-R produced a significant reduction in AT1 receptors. A single injection of the rAAV-AS (viral vector) was made in adult spontaneously hypertensive rats, either directly in the hypothalamus (1 µL) or in the lateral ventricles (5 µL). The result shows that there is a significant decrease of blood pressure (
23±2 mm Hg) for up to 9 weeks after injection. Control injections of mock vector produced no change in blood pressure during the same time period in age-matched controls. In young spontaneously hypertensive rats (3 weeks), a single intracardiac injection of recombinant rAAV-AS reduced blood pressure and slowed the development of hypertension compared with controls (P<.01). The results suggest that a prolonged reduction in high blood pressure can be achieved with AAV vectors delivering antisense to inhibit AT1 receptors with a single administration.
Key Words: recombinant adeno-associated virus (AAV) vector • AT1 receptor • antisense • hypertension • NG108-15 cells • angiotensin
Abbreviations: AAV = adeno-associated virus • Ang = angiotensin • AT = angiotensin II type • AT1-R = angiotensin II type 1 receptor • CMV = cytomegalovirus • GFP = green fluorescent protein • ICV = intracerebral ventricular • ITR = inverted terminal repeat • ODN = oligodeoxynucleotide • pAAV-AS = plasmid adeno-associated virus antisense • PCR = polymerase chain reaction • rAAV = recombinant adeno-associated virus • rAAV-AS = recombinant adeno-associated virus antisense • RT-PCR = reverse transcription-polymerase chain reaction • SBP = systolic blood pressure • SHR = spontaneously hypertensive rats
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