Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 207

Figure 5.1 Vectors used
in gene therapy clinical
trials.

%

23.9

20.8

25

%

17.7

20
15
10
5
0

8

6.7

5.7

4.4 4.8

3.4 3.2

1.4

Adeno-associated virus (AAV) vectors, being mildly immunogenic with an ability to
infect both dividing and nondividing cells without causing any disease, have become an
attractive strategy for gene delivery. An important issue with this vector is to develop effi-
cient production systems. Development of viral vectors requires critical analysis of the
biology and life cycle of the parental virus and the structure of the virus and its genome.
Vectors can be assessed with genetic analysis, in vitro experiments, but these may not
be predictive of their behavior in vivo. In vitro cultures are transformed, and even pri-
mary cells do not necessarily reflect the function of the same cells in vivo. Thus, it is
essential to perform extensive in vivo studies in animals to assess organ and cell targeting.
Currently, the available viral vectors cannot deliver efficiently, reproducibly, and stably a
foreign gene to specific renal compartments [1] .
Retrovirus vectors, adenovirus vectors, and AAV vectors are the only viral vec-
tors that have advanced to clinical trials aimed at developing gene therapy products
for their safety and biological function. Herpes viruses may soon be introduced into
clinical trials, but there is so far little formal preclinical biology or toxicology infor-
mation. Figure 5.1 summarizes worldwide reported viral vectors in gene therapy for
clinical trials up to December 2009.
Gene therapy in patients began with ex vivo approaches by taking advantage of the
stable integration of retrovectors to modify rapidly dividing cells (notably lympho-
cytes) that were then returned to the patient to treat either rare monogenic diseases,
for example, adenosine deaminase (ADA) deficiency, or a common acquired disease
such as cancer [1,2] . However, in vivo delivery systems have rapidly been adopted,
as is reflected in the use of adenovirus and AAV vectors [1] . Comparison of different
viral vectors are shown in Table 5.1 .

5.2 Adenovirus

Adenovirus was first isolated in 1953 [2] and was soon recognized as an invalu-
able tool for investigating mammalian molecular biology. Viruses of the family
Adenoviridae infect various species of vertebrates, including humans. Adenoviruses