PMID- 26942208
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160304
LR  - 20210317
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 3
DP  - 2016
TI  - AAV9-mediated central nervous system-targeted gene delivery via cisterna magna 
      route in mice.
PG  - 15055
LID - 10.1038/mtm.2015.55 [doi]
AB  - Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in 
      clinical trials for treating neurological disorders are its high expression in 
      many off-target tissues such as liver and heart, and lack of cell specificity 
      within the central nervous system (CNS) when using ubiquitous promoters such as 
      human cytomegalovirus (CMV) or chicken-beta-actin hybrid (CAG). To enhance targeting 
      the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, 
      scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and 
      CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters 
      exclusively targeted neurons in vitro, although their strengths were up to 
      10-fold lower than that of CMV. In vivo analyses of mouse tissue after scAAV9-GFP 
      vector delivery via the cisterna magna revealed a significant advantage of 
      synapsin 1 promoter over both Hb9 variants in targeting neurons throughout the 
      brain, since Hb9 promoters were driving gene expression mainly within the 
      motor-related areas of the brain stem. In summary, this study demonstrates that 
      cisterna magna administration is a safe alternative to intracranial or 
      intracerebroventricular vector delivery route using scAAV9, and introduces a 
      novel utility of the Hb9 promoter for the targeted gene expression for both in 
      vivo and in vitro applications.
FAU - Lukashchuk, Vera
AU  - Lukashchuk V
AD  - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, 
      University of Sheffield , Sheffield, UK.
FAU - Lewis, Katherine E
AU  - Lewis KE
AD  - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, 
      University of Sheffield , Sheffield, UK.
FAU - Coldicott, Ian
AU  - Coldicott I
AD  - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, 
      University of Sheffield , Sheffield, UK.
FAU - Grierson, Andrew J
AU  - Grierson AJ
AD  - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, 
      University of Sheffield , Sheffield, UK.
FAU - Azzouz, Mimoun
AU  - Azzouz M
AD  - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, 
      University of Sheffield, Sheffield, UK; Faculty of Applied Medical Sciences, King 
      Abdulaziz University, Jeddah, Saudi Arabia.
LA  - eng
GR  - G1001492/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20160217
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC4756767
EDAT- 2016/03/05 06:00
MHDA- 2016/03/05 06:01
PMCR- 2016/02/17
CRDT- 2016/03/05 06:00
PHST- 2015/07/30 00:00 [received]
PHST- 2015/12/07 00:00 [revised]
PHST- 2015/12/09 00:00 [accepted]
PHST- 2016/03/05 06:00 [entrez]
PHST- 2016/03/05 06:00 [pubmed]
PHST- 2016/03/05 06:01 [medline]
PHST- 2016/02/17 00:00 [pmc-release]
AID - S2329-0501(16)30145-0 [pii]
AID - 10.1038/mtm.2015.55 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2016 Feb 17;3:15055. doi: 10.1038/mtm.2015.55. 
      eCollection 2016.