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rupt the CCR5 locus of CD4+ T cells with high frequency, making them resistant
to HIV-1 infection [ 102 ]. However unlike lentiviral vectors, TALEN genes have
been shown to be packaged stably with a lower spontaneous recombination fre-
quency [ 23 ]. Also, multiple nucleases can be encoded in one efficacious vector
due to the large genome size of adenoviral vectors [ 103 ]. Moreover, as in the lenti-
viral vectors discussed earlier, adenoviral vectors have modified to change cell
type tropism. By modification of capsid components, the preference for liver tro-
pism for adenoviral vectors has been decreased as well as re-targeted to other cell
types, such as muscle cells [ 104 , 105 ].
1.4.2 Translational and Clinical Progress Using Adenoviral
Vectors
Adenoviral vectors were some of the first gene therapy tools used in clinical trials.
A vector delivering a correct CFTR gene, which had been delivered successfully in
rat epithelium, was trialed in humans in a landmark study [ 92 , 106 , 107 ]. While
gene transfer did occur, with measurable transcription of transgene mRNA, func-
tional replacement and symptomatic relief was not observed due to transient
expression of mRNA and the decreased efficacy upon repeat admissions of the
therapy (likely due to immunity associated against the vectors) [ 108 , 109 ]. Notably,
the first human death in a phase I viral gene therapy clinical trial occurred using
adenoviral vectors attempting to correct a metabolic deficiency that leads to ammo-
nia buildup. Jesse Gelsinger died shortly after administration of an adenoviral vec-
tor carrying an ornithine transcarbamylase gene after a severe reaction to the
infusion [ 110 ]. While there are still several questions surrounding the exact reasons
why Mr. Gelsinger had such a severe reaction, it has been proposed that his high
ammonia level pre-infusion could have contributed [ 111 ]. Mr. Gelsinger’s death
was a tragic setback in the field of gene therapy but has highlighted the importance
for stringency, informed consent, and quality practices in human gene therapy clin-
ical trials [ 111 , 112 ].
While the strong immune response that adenoviruses illicit in humans has beena challenge for gene delivery, it has also been used to the advantage of scientists
and clinicians. By expressing viral or bacterial antigens proteins using adenoviral
vectors, an immune response could be generated against the pathogen. Vaccination
using adenoviral expressed antigens of Mycobacterium tuberculosis has shown
stimulation of CD4+ and of CD8+ populations [ 113 ]. Similar approaches using
HIV-1 antigens have yet to show significant immune protection [ 114 ]. To circum-
vent this, groups have used adenoviral vectors to express neutralizing antigens to
HIV-1 intramuscularly, which have protected humanized mice from HIV-1 infec-
tion despite several high-titer exposures [ 115 ]. Another use for adenoviral vac-
cines has been to utilize them to help combat addiction to substances such as
J.E. DiCarlo et al.