Biomedical Engineering Reference
In-Depth Information
gene therapy research to move toward an effective clinical therapy
depends on many factors including the delivery method providing
accessibility of the CNS, timing of the transgene delivery, stability
of the transgene, specifi city of the vector, and safety profi les of the
vector as wells as the transgene. Thus far, viral vectors comprise the
most effective delivery system to the CNS. In fact, gene therapy
utilizing adeno-associated virus vectors (AAV) has shown a great
deal of benefi t in preclinical animal models of neurodegenerative
diseases [
1
-
9
] due to their ability to maintain long-term gene
expression by transducing postmitotic cells [
10
]. Recombinant
AAV (rAAV) serotype 2 is thus far the only serotype utilized in CNS
clinical trials and has been displayed a great safety profi le [
4
,
11
].
Since many other serotypes exhibit greater transduction and trans-
gene expression effi ciency than rAAV2 [
4
], choosing an optimal
serotype for a specifi c disease can be accomplished due to the fl ex-
ibility of AAV system which allows packaging of AAV2 terminal
repeats into the capsids of other serotypes [
12
]. Clinical trials for
neurological disorders include Parkinson's disease [
13
-
15
],
Alzheimer's disease [
16
,
17
], Canavan disease [
18
], and late infan-
tile neuronal ceroid lipofuscinosis (LINCL) [
19
]
Several neurodegenerative and neurodevelopmental disorders
are caused by the loss of function of a single gene such as Rett syn-
drome, Angelman syndrome, spinal muscular atrophy (SMA),
LINCL, mucopolysaccharidosis type III, Canavan disease, and
fragile X syndrome. Gene replacement through the administration
of a viral vector carrying the gene of interest has been envisioned
as a potential therapeutic for these and other monogenic diseases.
SMA, the most commonly inherited neurodegenerative disorder, is
caused by the loss of a gene called survival motor neuron 1 (
SMN1
)
leading to death of
-motor neurons in the ventral horn of the
spinal cord and subsequent atrophy of voluntary muscles. Even
though the gene causing the disease was identifi ed in 1995 [
20
],
the most effective gene therapy approach that led to the most sub-
stantial improvement in the life span of SMA mouse model was
developed in 2010 [
3
]. This strategy involved using a self-
complementary AAV (scAAV) serotype 9 expressing full-length
SMN cDNA [
3
,
21
-
24
]. The exciting outcome has made the shift
from the bench research to an actual treatment option a more real-
istic goal. The therapeutic benefi ts of scAAV9-SMN are currently
being examined in large animal models, and in September of 2013,
FDA has given the approval to Nationwide Children's Hospital for
phase I clinical trial of systemic AAV9 delivery of SMN gene.
Nevertheless, there are certain limitations of gene therapy to
achieve an effi cient level of rescue depending on (1) the vector
serotype, (2) the quantity and quality of the viral vector, (3) the
delivery route, and (4) the time of the application. Investigation of
the gene therapy limitations in mouse models mainly by
intracerebroventricular (ICV) delivery, which will be clinically
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