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Volume 8, Issue 2 (Suppl)
J Neurol Neurophysiol
ISSN: 2155-9562 JNN, an open access journal
Neurology 2017
March 27-29, 2017
March 27-29, 2017 Madrid, Spain
11
th
World Congress on
Neurology and Therapeutics
Plastin3 as a therapeutic target in spinal muscular atrophy
Aziza Al-Rafiah
King Abdul Aziza University, Saudi Arabia
S
pinal muscular atrophy (SMA) is a devastating childhood motor neuron disease caused by mutations in the survival motor neuron
1 gene
(SMN1). SMN1
and
SMN2
are nearly identical genes producing the survival of motor neuron (SMN) protein. SMN protein
plays a crucial role in mRNA splicing and β-actin mRNA transport along the axons. In SMA, the mutation leads to the loss of
SMN1
,
which cannot be fully compensated by the
SMN2
gene, which predominantly produces a truncated protein. The loss or reduction of
SMN protein leads to motor axonal defects and motor neuron cell death. There are currently no treatments available but therapies
have focused on increasing SMN through replacing SMN1 or increasing full length SMN from
SMN2
. The actin-binding protein
Plastin 3 (
PLS3
) has been reported as a modifier for SMA, making it a potential therapeutic target. Recently, it was shown that the
overexpression of the PLS3 gene improved axonal outgrowth in SMN- deficient motor neurons of SMA Zebra fish and cultured
motor neurons from mouse embryos. Gene therapy using viral vectors was carried out
in vitro
and
in vivo
to assess whether the
overexpression of
PLS3
could rescue neuronal loss in SMA and be developed as a therapy. The SMN☐7 mouse model produces low
levels of SMN, modelling severe SMA disease with an average lifespan of 12 days and loss of motor neurons. This study has established
that the SMNΔ7 mice have little or no detectable
PLS3
from birth, making it a good model for developing PLS3 gene therapy.
Lentiviral vectors were able to upregulate PLS3 expression in different cell lines. Transduction of NSC34 cells with LV-PLS3 vector led
to a five-fold increase in expression of PLS3 compared to controls. In smn-deficient MNs, expression of
PLS3
restored axonal length
and showed a strong neuroprotective effect. Pre-clinical in vivo proof-of-concept studies using adeno-associated virus serotype 9
(AAV9) encoding PLS3 in SMNΔ7 mice showed high transduction efficiency and overexpression of
PLS3
specifically targeted to
neurons in the central nervous system (CNS). This led to a small but significant increase of lifespan by 54%. However,
PLS3
was not
able to prevent disease onset. Although there was no improvement of phenotype, this study has demonstrated the potential use of
PLS3
as a target for gene therapy, possibly in conjunction with other modulators of disease.
aalrafiah@kau.edu.saAziza Al-Rafiah, J Neurol Neurophysiol 2017, 8:2 (Suppl)
http://dx.doi.org/10.4172/2155-9562.C1.046