124I-PET Assessment of Human Sodium Iodide Symporter Reporter Gene Activity for Highly Sensitive In Vivo Monitoring of Teratoma Formation in Mice

Lehner, S.; Lang, Cajetan Immanuel; Kaissis, Georgios; Todica, Andrei; Zacherl, Mathias J.; Boening, Guido; Spitzweg, Christine; Herbach, Nadja; Franz, Wolfgang-Michael; Krause, Bernd J.; Steinhoff, Gustav; Bartenstein, Peter; Hacker, Marcus; Dávid, Róbert

doi:10.1007/s11307-015-0857-1

Cited by 13 publications

(13 citation statements)

References 50 publications

(70 reference statements)

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“…However, they introduce the risk of forming teratomas. To study this phenomenon, Lehner and colleagues (153) generated murine PSCs stably expressing human NIS (hNIS) and injected them into mice to induce teratoma formation. By 124 I − PET, they monitored the growth of the teratomas and reported a correlation between tumor mass and tracer uptake.…”

Section: Nis As a Valuable Molecule To Monitor The Fate Of Stem Cellsmentioning

confidence: 99%

“…By 124 I − PET, they monitored the growth of the teratomas and reported a correlation between tumor mass and tracer uptake. They observed that hNIS expression and 124 I − did not affect the viability or the differentiation of PSCs and concluded that NIS-mediated 124 I − uptake can be used to monitor the formation of potential teratomas when PSCs are injected (153). …”

Section: Nis As a Valuable Molecule To Monitor The Fate Of Stem Cellsmentioning

confidence: 99%

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The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

Ravera

Reyna-Neyra

Ferrandino

et al. 2017

Annu. Rev. Physiol.

209

197

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Active iodide (I−) transport in both the thyroid and some extrathyroidal tissues is mediated by the N a+/I− symporter (NIS). In the thyroid, NIS-mediated I− uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. The molecular characterization of NIS in 1996 and the use of radioactive I− isotopes have led to significan advances in the diagnosis and treatment of thyroid cancer and provide the molecular basis for studies aimed at extending the use of radioiodide treatment in extrathyroidal malignancies. This review focuses on the most recent finding on I− homeostasis and I− transport deficiency-causin NIS mutations, as well as current knowledge of the structure/function properties of NIS and NIS regulatory mechanisms. We also discuss employing NIS as a reporter gene using viral vectors and stem cells in imaging, diagnostic, and therapeutic procedures.

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Section: Nis As a Valuable Molecule To Monitor The Fate Of Stem Cellsmentioning

confidence: 99%

Section: Nis As a Valuable Molecule To Monitor The Fate Of Stem Cellsmentioning

confidence: 99%

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

Ravera

Reyna-Neyra

Ferrandino

et al. 2017

Annu. Rev. Physiol.

209

197

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show abstract

“…hNIS is a relatively well-established radionuclide reporter gene that has been shown to track cells both in rodents 20 , 27 and in larger animals 15 , 17 . The feasibility to use hNIS for monitoring murine teratoma formation, after stable murine ESC transfection, has also been demonstrated by Lehner et al 28 . In contrast, hSSTr2 has not been frequently used for cell tracking.…”

Section: Discussionmentioning

confidence: 91%

The human somatostatin receptor type 2 as an imaging and suicide reporter gene for pluripotent stem cell-derived therapy of myocardial infarction

et al. 2018

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Rationale: Pluripotent stem cells (PSCs) are being investigated as a cell source for regenerative medicine since they provide an infinitive pool of cells that are able to differentiate towards every cell type of the body. One possible therapeutic application involves the use of these cells to treat myocardial infarction (MI), a condition where billions of cardiomyocytes (CMs) are lost. Although several protocols have been developed to differentiate PSCs towards CMs, none of these provide a completely pure population, thereby still posing a risk for neoplastic teratoma formation. Therefore, we developed a strategy to (i) monitor cell behavior noninvasively via site-specific integration of firefly luciferase (Fluc) and the human positron emission tomography (PET) imaging reporter genes, sodium iodide symporter (hNIS) and somatostatin receptor type 2 (hSSTr2), and (ii) perform hSSTr2-mediated suicide gene therapy via the clinically used radiopharmacon 177Lu-DOTATATE.Methods: Human embryonic stem cells (ESCs) were gene-edited via zinc finger nucleases to express Fluc and either hNIS or hSSTr2 in the safe harbor locus, adeno-associated virus integration site 1. Firstly, these cells were exposed to 4.8 MBq 177Lu-DOTATATE in vitro and cell survival was monitored via bioluminescence imaging (BLI). Afterwards, hNIS+ and hSSTr2+ ESCs were transplanted subcutaneously and teratomas were allowed to form. At day 59, baseline 124I and 68Ga-DOTATATE PET and BLI scans were performed. The day after, animals received either saline or 55 MBq 177Lu-DOTATATE. Weekly BLI scans were performed, accompanied by 124I and 68Ga-DOTATATE PET scans at days 87 and 88, respectively. Finally, hSSTr2+ ESCs were differentiated towards CMs and transplanted intramyocardially in the border zone of an infarct that was induced by left anterior descending coronary artery ligation. After transplantation, the animals were monitored via BLI and PET, while global cardiac function was evaluated using cardiac magnetic resonance imaging.Results: Teratoma growth of both hNIS+ and hSSTr2+ ESCs could be followed noninvasively over time by both PET and BLI. After 177Lu-DOTATATE administration, successful cell killing of the hSSTr2+ ESCs was achieved both in vitro and in vivo, indicated by reductions in total tracer lesion uptake, BLI signal and teratoma volume. As undifferentiated hSSTr2+ ESCs are not therapeutically relevant, they were differentiated towards CMs and injected in immune-deficient mice with a MI. Long-term cell survival could be monitored without uncontrolled cell proliferation. However, no improvement in the left ventricular ejection fraction was observed.Conclusion: We developed isogenic hSSTr2-expressing ESCs that allow noninvasive cell monitoring in the context of PSC-derived regenerative therapy. Furthermore, we are the first to use the hSSTr2 not only as an imaging reporter gene, but also as a suicide mechanism for radionuclide therapy in the setting of PSC-derived cell treatment.

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“…[16][17][18] Due to these desirable attributes, NIS has been used in many applications, such as tracking viral infection, replication, and spread in oncolytic virotherapy in animals and humans, tracking the intensity and durability of gene and cell therapies, and for treatment of NIS-expressing tumors with radioisotopes. 14,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Despite the growing utility of NIS as a reporter gene, there remain several challenges to NIS imaging and therapy. Endogenous NIS expression, efflux of radiotracer from NIS-expressing cells, and suboptimal NIS expression in target tissues decrease the efficacy of NIS imaging.…”

Section: Introductionmentioning

confidence: 99%

Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale

Concilio

Suksanpaisan²,

Pham

et al. 2021

Molecular Therapy

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The sodium iodide symporter (NIS) is widely used as a reporter gene to noninvasively monitor the biodistribution and durability of vector-mediated gene expression via gamma scintigraphy, single-photon emission computed tomography (SPECT), and positron-emission tomography (PET). However, the approach is limited by background signal due to radiotracer uptake by endogenous NIS-expressing tissues. In this study, using the SPECT tracer pertechnetate (99m TcO 4) and the PET tracer tetrafluoroborate (B 18 F 4), in combination with the NIS inhibitor perchlorate, we compared the transport properties of human NIS and minke whale (Balaenoptera acutorostrata scammoni) NIS in vitro and in vivo. Based on its relative resistance to perchlorate, the NIS protein from minke whale appeared to be the superior candidate reporter gene. SPECT and PET imaging studies in nude mice challenged with NIS-encoding adeno-associated virus (AAV)-9 vectors confirmed that minke whale NIS, in contrast to human and endogenous mouse NIS, continues to function as a reliable reporter even when background radiotracer uptake by endogenous NIS is blocked by perchlorate.

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124I-PET Assessment of Human Sodium Iodide Symporter Reporter Gene Activity for Highly Sensitive In Vivo Monitoring of Teratoma Formation in Mice

Cited by 13 publications

References 50 publications

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

The human somatostatin receptor type 2 as an imaging and suicide reporter gene for pluripotent stem cell-derived therapy of myocardial infarction

Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale

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