Editorial [Hot Topic :In Vivo Imaging & Gene Therapy (Guest Editor: Mark Tangney)]

One of the reasons why gene medicines have yet to reach the stage of licensed use in the West may be the lack of available robust methods to accurately monitor events post vector administration to patients. Traditional biopsy procedures have obvious limitations in assessing vector trafficking and transgene expression kinetics and levels, not least the impracticality of taking biopsy samples at multiple evaluation points or from every organ of interest. In response to the first gene therapy death, the NIH Recombinant DNA Advisory Committee (RAC) called for better assays for measuring transgene expression in cells and tissues [1]. Non-invasive imaging modalities are therefore under heavy investigation in recent years. By definition, molecular imaging (MI) techniques directly or indirectly monitor and record the spatio-temporal distribution of molecular and cellular processes for biochemical, biological, diagnostic or therapeutic applications (Radiological Society of North America and the Society of Nuclear Medicine) [2]. Use of MI stands to facilitate acquisition of the required data at various phases throughout the clinical protocol, in terms of both a) assessment of the location, magnitude and duration of transgene expression and b) monitoring of responses to intervention. Since the first conception of the radiotracer principle by George de Hevesy described in Nature in 1935 [3], a basis has existed for development of MI technology. Molecular imaging combines various disciplines, including cell biology, molecular biology, chemistry, physics and medicine. Only within the last decade have parallel developments in in vivo imaging technologies enabled routine use of MI modalities in pre-clinical and clinical settings. The reviews contained in this issue are not exhaustive with respect to the range of imaging technologies and reporter strategies pertinent to gene & cell therapy. The modalities of imaging technology used to detect reporter gene expression focused on in this issue include Optical, SPECT and PET, for imaging of various radio-tracers or light emissions. These represent the most widely used imaging modalities. Other clinical imaging technologies including MRI/MRS, exploiting a range of reporter genes are recently under investigation (for review, see [4]). However, the extent of this research in the context of gene therapy is limited, and the reviews presented in this issue focus on more established technologies. The various modalities differ in a number of key aspects, such as sensitivity; resolution (both spatial (μm - cm) and temporal (milliseconds to hours)); tomographic potential; depth penetration; availability of imaging probes; throughput level; cost; ease of operation; and potential for clinical transfer [4]. In the context of gene therapy, the most significant clinical progress has been made using PET and SPECT. While the sensitivity of PET imaging (see Collins et al. review) is high and the speed of imaging is relatively rapid (minutes), these techniques lack micrometer spatial resolution (1–2 mm with micro-PET). An alternative approach to PET is SPECT imaging (see review by Carlson et al.). While the sensitivity of the single-photon system can be two orders of magnitude less than the PET systems, the required radionuclides and hardware are more available. While not discussed in detail here, the advantage of MRI for potential imaging of gene expression is high 3D spatial resolution (tens of mm range); but sensitivity is low, requiring high concentrations of tracer and long exposure times. Overall, each method is not without its limitations, and there is certainly a need to develop protocols with improved signal sensitivity and resolution. Disadvantages of a given technique may be complemented through combination with another; e.g to provide highly sensitive molecular information (using PET or optical) with high spatial resolution (through MRI). Real-time imaging will be particularly beneficial to specify treatments to individual patients, particularly in the context of multigenic diseases such as cancer. Active collaboration between biological scientists, physicists, chemists and clinicians is required to drive the field forward to clinical use. The state-of-the-art as described here indicates that the translational jump for the current preclinical technologies may not be high.