The biology of the sodium iodide symporter and its potential for targeted gene delivery

Abstract

The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I)) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.

Fig. 1

Schematic representation of the role of NIS in iodide transport in normal thyroid follicular cells. Thyroid stimulating hormone (TSH) stimulation of TSH receptor (TSH-R) activates adenylate cyclase (AC) which generates cyclic AMP (cAMP) from AMP. This stimulates NIS-mediated co-transport of two sodium ions along with one iodide ion, with the transmembrane sodium gradient serving as the driving force for iodide uptake. Thiocyanate (CNS⁻) and perchlorate (ClO₄⁻) are competitive inhibitors of iodide accumulation in the thyroid. The efflux of iodide from the apical membrane to the follicular lumen is driven by pendrin (the Pendred syndrome gene product) and possibly other unknown apical transporters. Iodide organification within the thyroid follicular lumen (mediated by thyroperoxidase (TPO) and dual oxidase 2 (Duox2)) generates iodinated tyrosine residues within the thyroglobulin (Tg) backbone. These are ultimately released as active thyroid hormone (T3 and T4). (Modified from Spitzweg et al J. Clin. Endocrinol. Metab 2001 86, 3327–35).

Fig. 2

Secondary structure model of functional NIS protein. NIS is predicted to have 13 transmembrane domains with the NH₂ terminus facing extracellularly and the COOH terminus facing intracellularly. There are three potential glycosylation sites at positions 225, 485, and 497 of the amino acid sequence. The length of the 13 transmembrane segments ranges from 20–28 amino acids, except for transmembrane segment V which contains 18 residues. (Modified from Spitzweg et al J. Clin. Endocrinol. Metab 2001 86, 3327–35).

Fig. 3

Schematic diagram of adenovirus-mediated NIS gene delivery: 1. Ad-NIS is injected by the intratumoural, locoregional or systemic route; 2. Ad-NIS infects target cells through the cognate coxsackie and adenovirus receptor (CAR); 3. Ad-NIS drives NIS gene expression and protein is displayed on the cell membrane in infected cells.; 4. Radioiodine is administered systemically and is taken up in NIS-expressing tumour cells; 5. β-particulate radiation mediates both direct and bystander killing of cells.

Fig. 4

Possible interactions between NIS-mediated radioisotopic therapy and external beam radiotherapy (EBRT). EBRT increases CAR and integrin expression and enhances NIS gene expression from replication-defective adenoviral vectors. The radiation dose delivered via radioiodide, directly to transduced cells and indirectly to bystander cells, can sensitise these cells to the cytotoxic effects of EBRT. Additional use of targeted radiosensitising drugs can lead to further synergistic interactions between radioisotopic irradiation and EBRT.