15Additionally, much effort has been put into understanding the antigenic epitopes of
the AAV capsid by many experimental and computational schemes [ 150 ]. Targeting
AAV vectors to specific tissue types has largely been accomplished by identification
of naturally occurring AAV serotypes that efficiently transduce the organ/tissue of
interest [ 124 ]. The more scientists develop AAV vectors that utilize naturally occur-
ring serotype transduction efficiencies, consider cell surface glycan interactions with
AAV capsids, and engineer capsids through in vitro diversity generation and func-
tional selection, the more they will be able to generate highly specific and targeted
AAVs [ 124 , 151 – 153 ].
1.5.2 Translational and Clinical Progress Using
Adeno- associated Viral Vectors
With low toxicity, high transduction efficiencies across many tissue types, and fac-
ile manipulation, AAV vectors have become one of the most popular vectors for
human gene therapy [ 124 , 154 ]. As with adenoviral vectors, the first target for
clinical trials using AAV vectors based on AAV2 was for the delivery of the CFTR
gene in patients with cystic fibrosis [ 155 ]. Currently there are 173 recorded clinical
trials involving AAVs as gene therapy vectors [ 156 ]. Recently there have been
several successes using AAV vectors for gene therapy with effective therapeutic
outcomes. One of these was an scAAV8 vector encoding human clotting factor IX
for supplementation delivery to patients with Hemophilia B. Delivery of this vector
to ten patients resulted in factor IX levels 1–6% of normal factor IX values. In
patients who had a mean of 5.1 ± 1.7% of normal values of factor IX, there were
90% fewer bleeding events [ 157 ]. Another recent success involved AAV2 vectors
encoding RPE65 to supplement mutated RPE65 genes in patients with Leber’s
congenital amaurosis as well as in a canine model of the disease. AAV2-RPE65
vector resulted in modest but temporary improvements in retinal sensitivity in
patients and canine subjects [ 158 ]. Another important AAV vector therapy is the
treatment of lipoprotein lipase deficient patients using AAV1-LPLS447X, encoding a
gain-of-function lipoprotein lipase which was shown to resolve chylomicronemia
in lipoprotein lipase deficient mice. In a 2 year follow-up of a trial using this vec-
tor, Gaudet et al. showed that half of the treated patients showed a ≥40% reduction
in fasting triglycerides, resulting in a clinical benefit to the patients involved [ 159 ].
This vector has been approved in Europe for clinical use, making it the first gene
therapy ever approved in Europe or America. The vector, with the proprietary name
of Glybera, costs nearly $1 million dollars per treatment, making payment for this
treatment of a rare disease a serious consideration for patients and insurance com-
panies [ 160 , 161 ]. Looking forward, traditional AAV serotypes used for AAV vec-
tors will likely be modified and tailored more specifically for the tissue targets.
Recent success with AAV3-based engineered vectors suggests that they may be
superior for in vivo AAV gene therapy as compared to many traditional AAV
1 Viral Vectors, Engineered Cells and the CRISPR Revolution