TY - JOUR
T1 - Development of nonviral vectors targeting the brain as a therapeutic approach for Parkinson's disease and other brain disorders
AU - Javed, Hayate
AU - Menon, Sindhu A.
AU - Al-Mansoori, Karima M.
AU - Al-Wandi, Abdelmojib
AU - Majbour, Nour K.
AU - Ardah, Mustafa T.
AU - Varghese, Shiji
AU - Vaikath, Nishant N.
AU - Haque, M. Emdadul
AU - Azzouz, Mimoun
AU - El-Agnaf, Omar M.A.
N1 - Funding Information:
This work is supported by grant from Michael J. Fox Foundation for Parkinson's disease Research (NY, USA). The authors have declared that no conflict of interest exists. H.J., S.A.M., K.M.A., A.A., N.K.M., N.N.V., M.T.A., and S.V. performed the experiments. M.A. and O.M.A.E. designed, analyzed, and interpreted the experiments. M.E.H. contributed and advised on TH+ neurons counting and analysis. S.A.M. and O.M.A.E. wrote the manuscript. M.A. contributed to critical revision of the manuscript for important intellectual content.
Publisher Copyright:
© 2016 The American Society of Gene & Cell Therapy.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.
AB - Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.
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U2 - 10.1038/mt.2015.232
DO - 10.1038/mt.2015.232
M3 - Article
C2 - 26700614
AN - SCOPUS:84955595733
SN - 1525-0016
VL - 24
SP - 746
EP - 758
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -