PMID- 21364538
OWN - NLM
STAT- MEDLINE
DCOM- 20110930
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 19
IP  - 6
DP  - 2011 Jun
TI  - Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene 
      transfer.
PG  - 1070-8
LID - 10.1038/mt.2011.22 [doi]
AB  - We report the generation of a new class of adeno-associated virus serotype 9 
      (AAV9)-derived vectors displaying selective loss of liver tropism and 
      demonstrating potential for cardiac and musculoskeletal gene transfer 
      applications. Random mutagenesis of residues within a surface-exposed region of 
      the major AAV9 capsid protein yielded a capsid library with mutations clustered 
      at the icosahedral threefold symmetry axis. Using a combination of sequence 
      analysis, structural models, and in vivo screening, we identified several 
      functionally diverse AAV9 variants. The latter were classified into three 
      functional subgroups, with respect to parental AAV9 displaying: (i) decreased 
      transduction efficiency across multiple tissues; (ii) a selective decrease in 
      liver transduction, or (iii) a similar transduction profile. Notably, variants 
      9.45 and 9.61 (subgroup II) displayed 10- to 25-fold lower gene transfer 
      efficiency in liver, while transducing cardiac and skeletal muscle as efficiently 
      as AAV9. These results were further corroborated by quantitation of vector genome 
      copies and histological analysis of reporter (tdTomato) gene expression. The 
      study highlights the feasibility of generating AAV vectors with selectively 
      ablated tissue tropism, which when combined with other targeting strategies could 
      allow sharply segregated gene expression. Liver-detargeted AAV9 variants 
      described herein are excellent candidates for preclinical evaluation in animal 
      models of cardiac and musculoskeletal disease.
FAU - Pulicherla, Nagesh
AU  - Pulicherla N
AD  - Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, USA.
FAU - Shen, Shen
AU  - Shen S
FAU - Yadav, Swati
AU  - Yadav S
FAU - Debbink, Kari
AU  - Debbink K
FAU - Govindasamy, Lakshmanan
AU  - Govindasamy L
FAU - Agbandje-McKenna, Mavis
AU  - Agbandje-McKenna M
FAU - Asokan, Aravind
AU  - Asokan A
LA  - eng
GR  - HL089221/HL/NHLBI NIH HHS/United States
GR  - GM082926/GM/NIGMS NIH HHS/United States
GR  - R01 HL089221/HL/NHLBI NIH HHS/United States
GR  - HL089221-S1/S2/HL/NHLBI NIH HHS/United States
GR  - R01 GM082946/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110301
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
SB  - IM
CIN - Mol Ther. 2011 Jun;19(6):1006-7. PMID: 21629257
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Gene Transfer Techniques
MH  - Genetic Vectors/*genetics
MH  - HEK293 Cells
MH  - Humans
MH  - Liver/*metabolism
MH  - Mice
MH  - Muscle, Skeletal/*metabolism
MH  - Myocardium/*metabolism
PMC - PMC3129791
EDAT- 2011/03/03 06:00
MHDA- 2011/10/01 06:00
PMCR- 2012/06/01
CRDT- 2011/03/03 06:00
PHST- 2011/03/03 06:00 [entrez]
PHST- 2011/03/03 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - S1525-0016(16)31911-6 [pii]
AID - 10.1038/mt.2011.22 [doi]
PST - ppublish
SO  - Mol Ther. 2011 Jun;19(6):1070-8. doi: 10.1038/mt.2011.22. Epub 2011 Mar 1.