Raizada MK, Lu D, Iyer S, Katovich M
Losartan versus gene therapy: Chronic control of high blood
pressure in spontaneously hypertensive rats
50th Annual Fall Conference AHA Council for High Blood Pressure
Research
Hypertens
(Sep) 28:535 1996
(also reviewed is the following related abstract from the same
meeting:
Prolonged reduction of high blood pressure with an in vivo
nonpathogenic, adeno-associated viral vector delivery of AT1-R mRNA
antisense. by M. I. Phillips, D. Mohuczy-Dominiack, S. Galli, T.
Zelles, Univ. Florida. Hypertension 7: 535, 1996.)
Despite a rather large armamentarium of effective anti-hypertensive
agents, the pharmacologic treatment for systemic hypertension is still
fraught with difficulties. Patients must take life-long medication,
often two, three or four time a day. In addition to problems with
compliance, these therapies have significant side effects.
These two remarkable studies are the first reports of using gene
therapy to treat hypertension in laboratory animals. Both studies use
the spontaneously hypertensive rat (SHR) model of hypertension, which
develop reproducible hypertension which is responsive to the
angiotensin (AT-1) receptor antagonist Losartan. These abstracts from
the same institution take two different approaches.
The first abstract uses a retrovirus containing the 'anti-sense'
portion of the AT-1 receptor to inhibit expression of the AT-1
receptor. The virus was given once at 5 days of life to SHR and
control (WKY) rats. This single injection decreased expression and
function of the AT-1 receptor protein for 90 days. The lack of
receptor function was documented by finding decreases in AT-1
stimulated thirst and pressor responses. Blood pressure was decreased
by 30-40 mmHg at 90 days post treatment, with no changes in the
control rats. Finally, treatment with Losartan failed to drop blood
pressure, indicating that the genetic intervention had produced a
maximal anti-hypertensive effect. Thus, a single intravenous
injection produced long term 3 months control of hypertension.
Imagine the possibilities .....
The second report uses a different viral vector injected into the
brain, but also achieves prolonged (5 weeks) reduction in blood
pressure. They injected an adeno-associated virus which also
contained the anti-sense portion of the AT-1 receptor. This
particular virus does not stimulate inflammation or an immune
response, both of which limit the effectiveness and duration of
biological effect. A single injection of the vector was given to
adult SHR or WKY rats either into the hypothalamus or into the lateral
ventricles. The blood pressure was reduced for up to 5 weeks post
injection. While this approach is less clinically useful because of
the hazards of the brain injections, it nevertheless indicated that a
prolonged reduction in high blood pressure can be achieved with
vectors delivering the antisense DNA to the AT1 receptors.
Comment: Obviously, more work needs to be performed to
determine the optimal viral vector, site of injection, method of
delivery, and target gene. However, these exciting results are but a
mere glimpse of the future of medical practices. An exciting time we
live in... (Robert A. Star, M.D., University of Texas Southwestern
Medical Center)
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50th Annual Fall Conference AHA Council for High Blood Pressure
Research
H: Pathophysiology :
Genetics