Developing MR reporter genes: promises and pitfalls

MR reporter genes have the potential to monitor transgene expression non-invasively in real time at high resolution. These genes can be applied to interrogate the efficacy of gene therapy, to assess cellular differentiation, cell trafficking, and specific metabolic activity, and also assess changes in the microenvironment. Efforts toward the development of MR reporter genes have been made for at least a decade, but, despite these efforts, the field is still in its early developmental stage. This reflects the fact that there are potential pitfalls, caused by the low sensitivity of detection, the need for substrates with their associated undesirable pharmacokinetics, and/or the difficult and, in some cases, delayed interpretation of signal changes. Nevertheless, significant progress has been made during the last few years. Whereas enzyme-based reporters were initially applied to NMR spectroscopic monitoring of changes in phosphor and fluorine metabolism, MRI-based approaches are now emerging that rely on: (1) enzyme-based cleavage of functional groups that block water (proton) exchange or protein binding of MR contrast agents; (2) expression of surface receptors that enable binding of specific MR contrast agents; (3) expression of para- and anti-ferromagnetic (metallo)proteins involved with iron metabolism, such as tyrosinase, transferrin receptor, and ferritin. After an introduction to the basic principles of designing promoters, expression vectors, and cloning of transgenes, a fresh look is provided on the use of reporter genes for optical (including bioluminescent) and nuclear imaging, with which MR reporter genes compete. Although progress in the use of MR reporter genes has been slow, newer strategies that use metalloproteins or alternative contrast mechanisms, with no need for substrates, promise rapid growth potential for this field.