The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment

Abstract

Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past 2 decades significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery, towards promising new applications in disseminated disease, in particular, through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

Structural insights into the mechanism of the sodium/iodide symporter (NIS)

“…There is great interest in exogenously expressing NIS in cancers that do not express it endogenously so that those cancers become sensitives to radioiodide therapy 3,5 . That would require that patients will have their endogenous thyroidal NIS expression downregulated by the administration of thyroid hormones to prevent damage to their thyroid.…”

“…Indeed, because NIS accumulates its substrates in the cell, it offers higher detection sensitivity than proteins that only bind their ligands stoichiometrically. As a result, NIS is becoming the counterpart of green fluorescent protein (GFP) or luciferase for imaging studies in humans 3,5,7,8 . Although the physiology, biochemistry, biophysics, and cell biology of NIS have all been investigated extensively 1,3 , our understanding of its symport mechanism has, until now, been hindered by a lack of high-resolution structures of NIS.…”

“…Thyroid cancer patients are often treated with 131 I - after thyroidectomy: this therapy targets and kills remnant malignant cells that actively accumulate the radioisotope via NIS. Because 131 I - treatment of thyroid cancer is so effective and has only relatively minor side effects, there is great interest 3 in expressing NIS exogenously in cancers that do not express it endogenously to render them susceptible to destruction by 131 I - 5 . In addition, NIS is functionally expressed endogenously not only in several extrathyroidal tissues—such as the salivary glands, stomach, intestine, and lactating breast—but also in primary and metastatic breast cancers 6 .…”

Selective sodium iodide symporter (NIS) gene therapy of glioblastoma mediated by EGFR-targeted lipopolyplexes

“… 10 , 17 , 64 , 65 This is one of the major advantages of NIS as a therapy gene and makes the approach highly effective. 66 Ex vivo staining for blood vessel density demonstrated a long-term antiangiogenic therapeutic effect of 131 I treatment. The vascularization status of a tumor influences the growth rate.…”

Radioiodine: 80 years and counting; the past, present, and future

“…Moving beyond thyroid cancer, there is the possibility that NIS can be expressed in other forms of cancer to enable radionuclide imaging and radioiodine therapy in cancers that do not normally express NIS. Spitzweg et al (2021) review the experience of facilitating exogenous NIS expression in a variety of cancer types using viral and now synthetic vectors to target NIS expression in non-thyroid cancers. If successful, this will further expand the use of radioiodine well beyond its original utilization in goiter, hyperthyroidism, and thyroid cancer.…”