PMID- 31296047
OWN - NLM
STAT- MEDLINE
DCOM- 20200427
LR  - 20201016
IS  - 1942-0080 (Electronic)
IS  - 1941-9651 (Print)
IS  - 1941-9651 (Linking)
VI  - 12
IP  - 7
DP  - 2019 Jul
TI  - Noninvasive In Vivo Quantification of Adeno-Associated Virus Serotype 9-Mediated 
      Expression of the Sodium/Iodide Symporter Under Hindlimb Ischemia and 
      Neuraminidase Desialylation in Skeletal Muscle Using Single-Photon Emission 
      Computed Tomography/Computed Tomography.
PG  - e009063
LID - 10.1161/CIRCIMAGING.119.009063 [doi]
AB  - BACKGROUND: We propose micro single-photon emission computed tomography/computed 
      tomography imaging of the hNIS (human sodium/iodide symporter) to noninvasively 
      quantify adeno-associated virus 9 (AAV9)-mediated gene expression in a murine 
      model of peripheral artery disease. METHODS: AAV9-hNIS (2x10(11) viral genome 
      particles) was injected into nonischemic or ischemic gastrocnemius muscles of 
      C57Bl/6J mice following unilateral hindlimb ischemia +/- the alpha-sialidase NA 
      (neuraminidase). Control nonischemic limbs were injected with phosphate buffered 
      saline or remained noninjected. Twelve mice underwent micro single-photon 
      emission computed tomography/computed tomography imaging after serial injection 
      of pertechnetate ((99m)TcO(4)(-)), a NIS substrate, up to 28 days after AAV9-hNIS 
      injection. Twenty four animals were euthanized at selected times over 1 month for 
      ex vivo validation. Forty-two animals were imaged with (99m)TcO(4)(-) +/- the 
      selective NIS inhibitor perchlorate on day 10, to ascertain specificity of 
      radiotracer uptake. Tissue was harvested for ex vivo validation. A modified 
      version of the U-Net deep learning algorithm was used for image quantification. 
      RESULTS: As quantitated by standardized uptake value, there was a gradual 
      temporal increase in (99m)TcO(4)(-) uptake in muscles treated with AAV9-hNIS. 
      Hindlimb ischemia, NA, and hindlimb ischemia plus NA increased the magnitude of 
      (99m)TcO(4)(-) uptake by 4- to 5-fold compared with nonischemic muscle treated 
      with only AAV9-hNIS. Perchlorate treatment significantly reduced (99m)TcO(4)(-) 
      uptake in AAV9-hNIS-treated muscles, demonstrating uptake specificity. The 
      imaging results correlated well with ex vivo well counting (r(2)=0.9375; 
      P<0.0001) and immunoblot analysis of NIS protein (r(2)=0.65; P<0.0001). 
      CONCLUSIONS: Micro single-photon emission computed tomography/computed tomography 
      imaging of hNIS-mediated (99m)TcO(4)(-) uptake allows for accurate in vivo 
      quantification of AAV9-driven gene expression, which increases under ischemic 
      conditions or neuraminidase desialylation in skeletal muscle.
FAU - Boutagy, Nabil E
AU  - Boutagy NE
AD  - Department of Medicine, Section of Cardiovascular Medicine, Yale Translational 
      Research Imaging Center (N.E.B., Z.W.Z., A.F., M.R.S., A.J.S.), Yale School of 
      Medicine, New Haven, CT.
FAU - Ravera, Silvia
AU  - Ravera S
AD  - Department of Cellular and Molecular Physiology (S.R., N.C.), Yale School of 
      Medicine, New Haven, CT.
FAU - Papademetris, Xenophon
AU  - Papademetris X
AD  - Department of Radiology and Biomedical Imaging (X.P., J.A.O., J.W., A.J.S.), Yale 
      School of Medicine, New Haven, CT.
FAU - Onofrey, John A
AU  - Onofrey JA
AD  - Department of Radiology and Biomedical Imaging (X.P., J.A.O., J.W., A.J.S.), Yale 
      School of Medicine, New Haven, CT.
FAU - Zhuang, Zhen W
AU  - Zhuang ZW
AD  - Department of Medicine, Section of Cardiovascular Medicine, Yale Translational 
      Research Imaging Center (N.E.B., Z.W.Z., A.F., M.R.S., A.J.S.), Yale School of 
      Medicine, New Haven, CT.
FAU - Wu, Jing
AU  - Wu J
AD  - Department of Radiology and Biomedical Imaging (X.P., J.A.O., J.W., A.J.S.), Yale 
      School of Medicine, New Haven, CT.
FAU - Feher, Attila
AU  - Feher A
AD  - Department of Medicine, Section of Cardiovascular Medicine, Yale Translational 
      Research Imaging Center (N.E.B., Z.W.Z., A.F., M.R.S., A.J.S.), Yale School of 
      Medicine, New Haven, CT.
FAU - Stacy, Mitchel R
AU  - Stacy MR
AD  - Department of Medicine, Section of Cardiovascular Medicine, Yale Translational 
      Research Imaging Center (N.E.B., Z.W.Z., A.F., M.R.S., A.J.S.), Yale School of 
      Medicine, New Haven, CT.
FAU - French, Brent A
AU  - French BA
AD  - Department of Biomedical Engineering (B.A.F., B.H.A.), University of Virginia, 
      Charlottesville.
AD  - Division of Cardiovascular Medicine, Department of Medicine (B.A.F., B.H.A.), 
      University of Virginia, Charlottesville.
FAU - Annex, Brian H
AU  - Annex BH
AD  - Department of Biomedical Engineering (B.A.F., B.H.A.), University of Virginia, 
      Charlottesville.
AD  - Division of Cardiovascular Medicine, Department of Medicine (B.A.F., B.H.A.), 
      University of Virginia, Charlottesville.
FAU - Carrasco, Nancy
AU  - Carrasco N
AD  - Department of Cellular and Molecular Physiology (S.R., N.C.), Yale School of 
      Medicine, New Haven, CT.
FAU - Sinusas, Albert J
AU  - Sinusas AJ
AD  - Department of Medicine, Section of Cardiovascular Medicine, Yale Translational 
      Research Imaging Center (N.E.B., Z.W.Z., A.F., M.R.S., A.J.S.), Yale School of 
      Medicine, New Haven, CT.
AD  - Department of Radiology and Biomedical Imaging (X.P., J.A.O., J.W., A.J.S.), Yale 
      School of Medicine, New Haven, CT.
LA  - eng
GR  - R24 MH114805/MH/NIMH NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
GR  - R01 DK041544/DK/NIDDK NIH HHS/United States
GR  - S10 OD021845/OD/NIH HHS/United States
GR  - T32 HL098069/HL/NHLBI NIH HHS/United States
GR  - R01 HL116455/HL/NHLBI NIH HHS/United States
GR  - R01 HL141325/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190712
PL  - United States
TA  - Circ Cardiovasc Imaging
JT  - Circulation. Cardiovascular imaging
JID - 101479935
RN  - 0 (Saline Solution)
RN  - 0 (Symporters)
RN  - 4XE5NDT4K1 (sodium-iodide symporter)
RN  - EC 3.2.1.18 (Neuraminidase)
SB  - IM
CIN - Circ Cardiovasc Imaging. 2019 Jul;12(7):e009452. PMID: 31296046
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/*physiology
MH  - Hindlimb/blood supply
MH  - Ischemia
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Muscle, Skeletal/diagnostic imaging/*metabolism
MH  - Neuraminidase/*metabolism
MH  - Peripheral Arterial Disease/*metabolism
MH  - Saline Solution/administration & dosage
MH  - Single Photon Emission Computed Tomography Computed Tomography/*methods
MH  - Symporters/*pharmacokinetics
PMC - PMC6629470
MID - NIHMS1532042
OTO - NOTNLM
OT  - animals
OT  - genetic therapy
OT  - neuraminidase
OT  - peripheral artery disease
OT  - tomography, emission computed, single-photon
EDAT- 2019/07/13 06:00
MHDA- 2020/04/28 06:00
PMCR- 2020/07/12
CRDT- 2019/07/13 06:00
PHST- 2019/07/13 06:00 [entrez]
PHST- 2019/07/13 06:00 [pubmed]
PHST- 2020/04/28 06:00 [medline]
PHST- 2020/07/12 00:00 [pmc-release]
AID - 10.1161/CIRCIMAGING.119.009063 [doi]
PST - ppublish
SO  - Circ Cardiovasc Imaging. 2019 Jul;12(7):e009063. doi: 
      10.1161/CIRCIMAGING.119.009063. Epub 2019 Jul 12.