Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 291

6.5 Applications of Gene Therapy in Cardiovascular
Diseases
The applications of gene therapy have also been extended to CV diseases. CV diseases
are the leading cause of mortalities in western countries. A number of therapies are
available in clinical practice for CV disorders, but they do not cure the basic cause of
the disease [192] . Gene therapy is specifically important for monogenetic CV disor-
ders like hypertension [193] or hypercholesterolemia [194] because the primary goal
of gene therapy is to insert the corrected form of the mutated gene into the appropriate
target cell type to restore normal function. However, for polygenetic CV disorders it
is difficult to replace malfunctioning genes using gene therapy, but gene therapy can
offer an alternative or adjunct treatment to conventional pharmacological approaches.
There are certain specific advantages of using gene therapy for CV disorders such
as easy accessibility of blood vessels; in most disorders, only a temporary expression
of the transfected gene will be required to achieve a beneficial biological effect. In
addition, gene therapy can be used as a molecular tool to probe pathways and mecha-
nisms that are difficult to elucidate by other means. The applications of gene therapy
in certain CV diseases are discussed below.
6.5.1 Hypertension
Hypertension is characterized by elevated levels of blood pressure, which may be
caused by several polygenic and environmental factors. This leads to a number of CV
diseases like cardiac failure, atherosclerosis, and stroke, to name a few. The various
components of the renin-angiotensin system (RAS) in brain and peripheral vasculature
are the primary targets of gene therapy in hypertension. Renin stimulates the synthe-
sis of angiotensin I (Ang I) from angiotensinogen (AGT), which is further converted
into angiotensin II (Ang II), an active octapeptide, by the angiotensin-converting
enzyme (ACE). Angiotensin II acts on two receptors, namely, angiotensin type 1
receptors (AT1R) and angiotensin type 2 receptors (AT2R) [195] .
The antisense oligonucleotide (AS-ODNs) strategy was developed against over-
active proteins and acts as a drug target in hypertension. For example, AS-ODNs to
AT1R, when given in central RAS, reduced blood pressure to a significant extent in
various rat hypertension models like the spontaneous hypertension rats model (SHR),
the cold-induced hypertension model, the environmental model, and the two-kidney
one-clip model [196,197] . Similarly, when AT1 AS-ODNs were given to peripheral
circulation, it resulted in reduced blood pressure in the arteries of the two-kidney one-
clip hypertension rat models [198] . The use of adenovirus and lentivirus for the deliv-
ery of AT1 AS-mRNA resulted in long-term expression and persistent lowering of
blood pressure in rat models [199,200] . AS-ODNs against AGT [201] ACE-AS-ODN
[202] , renin-AS-ODN [203] , and 1-AS-ODN [204] also showed promising results
in various hypertension models in rats. Apart from the RES system, various enzymes
like endothelial nitric oxide synthase (eNOS) and extracellular superoxide dismutase
(EC-SOD) have also shown a predominant role in human hypertension by reducing