Radionuclide-based reporter gene imaging: pre-clinical and clinical implementation and application

Noninvasive reporter gene imaging using radiolabeled probes was first described in 1995, and requires “pre-targeting” (delivery) of the reporter construct to the target tissue (by transfection/transduction). In each case, the reporter system involves a “complimentary pair”; a reporter gene construct and a complimentary radiolabeled probe or substrate. The most widely used reporter gene, HSV1-tk (and a variety of mutants, such as HSV1-tksr39), utilizes enzymatic amplification through phosphorylation and trapping of a specific radiolabeled probe (such as [124I]FIAU or [18F]FHBG), similar to imaging hexokinase activity with [18F]FDG. Recent attention as turned to “human” reporter genes to avoid a potential immunological response to a foreign protein; seven human reporter genes are briefly discussed. Reporter gene imaging can provide non-invasive assessments of endogenous biological processes in living subjects. At least two Radionuclide-based reporter gene imaging: pre-clinical and clinical implementation and application Correspondence to: Dr. Ronald G. Blasberg, MD Departments of Neurology and Radiology, MH (Box 52) Molecular Pharmacology & Chemistry Program, SKI Memorial Sloan Kettering Cancer Center (MSKCC) 415 East 68th Street, New York, NY 10065 Tel: 646 888–2211 Fax: (646) 422-0408 E-mail: blasberg@neuro1.mskcc. org Inna Serganova1, Vladimir Ponomarev2, 3, Ronald G. Blasberg1–3 1Department of Neurology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 2Department of Radiology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 3Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York Grant Support: This manuscript was supported by NIH research grants 2P50CA086438-11, 1R01CA163980-01A1, R01 CA161138-01, and 5P01CA094060-10 different reporter constructs will be required in most future applications of reporter gene imaging. One will be a “constitutive” reporter that will be used to identify the site, extent and duration of vector delivery and tissue transduction or for identifying the cell distribution/trafficking, homing/targeting and persistence (the “normalizing” or denominator term). The second one will be an “inducible” reporter that is sensitive to endogenous transcription factors, signaling pathways or protein-protein interactions that monitor the biological activity and function of the transduced cells (the “sensor” or numerator term). The initial applications of reporter gene imaging in patients will be developed within two different clinical disciplines: 1. gene therapy and 2. adoptive cell-based therapies. These studies will benefit from the availability of efficient human reporter systems that can provide critical monitoring information for adeno-, retroand lenteviral-based gene therapy, oncolytic bacterial and viral therapy, and adoptive cell-based therapies. The translational applications of noninvasive in vivo reporter gene imaging are likely to include: 1. quantitative monitoring of the gene therapy vector and transduction efficacy in clinical protocols by imaging the location, extent and duration of transgene expression; 2. monitoring cell trafficking, targeting, replication and activation in adoptive T cell and stem/progenitor cell therapies; 3. assessments of endogenous molecular events using different inducible reporter gene imaging systems.