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The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy.

ABSTRACT: Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [¹²⁴I]iodide ([¹²⁴I]NaI) or [¹⁸F]tetrafluoroborate ([¹⁸F]TFB). We performed a small preclinical PET imaging study comparing sodium [¹²⁴I]iodide and in-house synthesized [¹⁸F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [¹⁸F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma.Trial registration not applicable.

SUBMITTER: Kitzberger C

PROVIDER: S-EPMC9065223 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy.

Kitzberger Carolin C Spellerberg Rebekka R Morath Volker V Schwenk Nathalie N Schmohl Kathrin A KA Schug Christina C Urnauer Sarah S Tutter Mariella M Eiber Matthias M Schilling Franz F Weber Wolfgang A WA Ziegler Sibylle S Bartenstein Peter P Wagner Ernst E Nelson Peter J PJ Spitzweg Christine C

EJNMMI research 20220503 1

Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and gene ...[more]

PMID: 35503582

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Project description:BACKGROUND:Iodide that is essential for thyroid hormone synthesis is actively transported into the thyroid follicular cells via sodium/iodide symporter (NIS) protein in vertebrates. It is well known that NIS expression in thyroid is regulated by the thyroid statuses mainly through thyroid stimulating hormone (TSH). Although NIS mRNA expressions in extrathyroidal tissues have been qualitatively reported, their regulation by thyroid statuses has not been well clarified. METHODS:Male ICR mice aged four weeks were assigned into three groups (control, hypothyroid, and hyperthyroid). Hypothyroid group of mice were treated with 0.02% methimazole in drinking water and hyperthyroid group of mice received intraperitoneal injection (4 mug L-T4 twice a week) for four weeks. NIS mRNA expression levels in the tissues were evaluated using Northern blot hybridization and quantitative real-time RTPCR (qPCR). Additionally, end-point RTPCR for the thyroid follicular cell-characteristic genes (TSH receptor, TSHR; thyroid transcription factor-1, TTF1; and paired box gene 8, Pax8) was carried out. RESULTS:By Northern blot analysis, NIS mRNA was detected in thyroid and stomach. In addition to these organs, qPCR revealed the expression also in the submandibular gland, colon, testis, and lung. Expression of NIS mRNA in thyroid was significantly increased in hypothyroid and decreased in hyperthyroid group. Trends of NIS mRNA expression in extrathyroidal tissues were not in line with that in the thyroid gland in different thyroid statuses. Only in lung, NIS mRNA was regulated by thyroid statuses but in opposite way compared to the manner in the thyroid gland. There were no extrathyroidal tissues that expressed all three characteristic genes of thyroid follicular cells. CONCLUSIONS:NIS mRNA expression in the thyroid gland was up-regulated in hypothyroid mice and was down-regulated in hyperthyroid mice, suggesting that NIS mRNA in the thyroid gland is regulated by thyroid statuses. In contrast, NIS mRNA expression in extrathyroidal tissues was not altered by thyroid statuses although it was widely expressed. Lack of responsiveness of NIS mRNA expressions in extrathyroidal tissues reemphasizes additional functions of NIS protein in extrathyroidal tissues other than iodide trapping.

Project description:The sodium iodide symporter (NIS) transports iodide, which is necessary for thyroid hormone production. NIS also transports other monovalent anions such as tetrafluoroborate (BF4-), pertechnetate (TcO4-), and thiocyanate (SCN-), and is competitively inhibited by perchlorate (ClO4-). However, the mechanisms of substrate selectivity and inhibitor sensitivity are poorly understood. Here, a comparative approach was taken to determine whether naturally evolved NIS proteins exhibit variability in their substrate transport properties. The NIS proteins of thirteen animal species were initially assessed, and three species from environments with differing iodide availability, freshwater species Danio rerio (zebrafish), saltwater species Balaenoptera acutorostrata scammoni (minke whale), and non-aquatic mammalian species Homo sapiens (human) were studied in detail. NIS genes from each of these species were lentivirally transduced into HeLa cells, which were then characterized using radioisotope uptake assays, 125I- competitive substrate uptake assays, and kinetic assays. Homology models of human, minke whale and zebrafish NIS were used to evaluate sequence-dependent impact on the organization of Na+ and I- binding pockets. Whereas each of the three proteins that were analyzed in detail concentrated iodide to a similar degree, their sensitivity to perchlorate inhibition varied significantly: minke whale NIS was the least impacted by perchlorate inhibition (IC50 = 4.599 μM), zebrafish NIS was highly sensitive (IC50 = 0.081 μM), and human NIS showed intermediate sensitivity (IC50 = 1.566 μM). Further studies with fifteen additional substrates and inhibitors revealed similar patterns of iodide uptake inhibition, though the degree of 125I- uptake inhibition varied with each compound. Kinetic analysis revealed whale NIS had the lowest Km-I and the highest Vmax-I. Conversely, zebrafish NIS had the highest Km and lowest Vmax. Again, human NIS was intermediate. Molecular modeling revealed a high degree of conservation in the putative ion binding pockets of NIS proteins from different species, which suggests the residues responsible for the observed differences in substrate selectivity lie elsewhere in the protein. Ongoing studies are focusing on residues in the extracellular loops of NIS as determinants of anion specificity. These data demonstrate significant transport differences between the NIS proteins of different species, which may be influenced by the unique physiological needs of each organism. Our results also identify naturally-existing NIS proteins with significant variability in substrate transport kinetics and inhibitor sensitivity, which suggest that the affinity and selectivity of NIS for certain substrates can be altered for biotechnological and clinical applications. Further examination of interspecies differences may improve understanding of the substrate transport mechanism.

Project description:The vertebrate sodium-iodide symporter (NIS or SLC5A5) transports iodide into the thyroid follicular cells that synthesize thyroid hormone. The SLC5A protein family includes transporters of vitamins, minerals, and nutrients. Disruption of SLC5A5 function by perchlorate, a pervasive environmental contaminant, leads to human pathologies, especially hypothyroidism. Perchlorate also disrupts the sexual development of model animals, including threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio), but the mechanism of action is unknown. To test the hypothesis that SLC5A5 paralogs are expressed in tissues necessary for the development of reproductive organs, and therefore are plausible candidates to mediate the effects of perchlorate on sexual development, we first investigated the evolutionary history of Slc5a paralogs to better understand potential functional trajectories of the gene family. We identified two clades of slc5a paralogs with respect to an outgroup of sodium/choline cotransporters (slc5a7); these clades are the NIS clade of sodium/iodide and lactate cotransporters (slc5a5, slc5a6, slc5a8, slc5a8, and slc5a12) and the SGLT clade of sodium/glucose cotransporters (slc5a1, slc5a2, slc5a3, slc5a4, slc5a10, and slc5a11). We also characterized expression patterns of slc5a genes during development. Stickleback embryos and early larvae expressed NIS clade genes in connective tissue, cartilage, teeth, and thyroid. Stickleback males and females expressed slc5a5 and its paralogs in gonads. Single-cell transcriptomics (scRNA-seq) on zebrafish sex-genotyped gonads revealed that NIS clade-expressing cells included germ cells (slc5a5, slc5a6a, and slc5a6b) and gonadal soma cells (slc5a8l). These results are consistent with the hypothesis that perchlorate exerts its effects on sexual development by interacting with slc5a5 or its paralogs in reproductive tissues. These findings show novel expression domains of slc5 genes in stickleback and zebrafish, which suggest similar functions across vertebrates including humans, and provide candidates to mediate the effects of perchlorate on sexual development.

Project description:Background: The ability of thyroid follicular epithelial cells to accumulate iodide via the sodium/iodide symporter (NIS) is exploited to successfully treat most thyroid cancers, although a subset of patients lose functional NIS activity and become unresponsive to radioiodide therapy, with poor clinical outcome. Our knowledge of NIS regulation remains limited, however. While numerous membrane proteins are functionally regulated via dimerization, there is little definitive evidence of NIS dimerization, and whether this might impact upon radioiodide uptake and treatment success is entirely unknown. We hypothesized that NIS dimerizes and that dimerization is a prerequisite for iodide uptake. Methods: Coimmunoprecipitation, proximity ligation, and Förster resonance energy transfer (FRET) assays were used to assess NIS:NIS interaction. To identify residues involved in dimerization, a homology model of NIS structure was built based on the crystal structure of the dimeric bacterial protein vSGLT. Results: Abundant cellular NIS dimerization was confirmed in vitro via three discrete methodologies. FRET and proximity ligation assays demonstrated that while NIS can exist as a dimer at the plasma membrane (PM), it is also apparent in other cellular compartments. Homology modeling revealed one key potential site of dimeric interaction, with six residues <3Å apart. In particular, NIS residues Y242, T243, and Q471 were identified as critical to dimerization. Individual mutation of residues Y242 and T243 rendered NIS nonfunctional, while abrogation of Q471 did not impact radioiodide uptake. FRET data show that the putative dimerization interface can tolerate the loss of one, but not two, of these three clustered residues. Conclusions: We show for the first time that NIS dimerizes in vitro, and we identify the key residues via which this happens. We hypothesize that dimerization of NIS is critical to its trafficking to the PM and may therefore represent a new mechanism that would need to be considered in overcoming therapeutic failure in patients with thyroid cancer.

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The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy.

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The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy.

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