Methods to monitor gene therapy with molecular imaging

Waerzeggers, Yannic; Monfared, Parisa; Viel, Thomas; Winkeler, Alexandra; Voges, Jürgen; Jacobs, Andréas H.

doi:10.1016/j.ymeth.2009.03.007

Cited by 63 publications

(54 citation statements)

References 140 publications

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“…Magnetic resonance imaging (MRI) has a number of important advantages over other non-invasive imaging modalities, described in detail by Waerzeggers et al 100 but are summarized as follows; (i) it has relatively high three-dimensional spatial resolution when compared with PET (ii) it has very good sample penetration in multiple imaging planes, (iii) it has the ability to measure more than one physiological parameter using different radiofrequency pulse sequences, (iv) it has no risk of ionizing radiation and (v) it is already widely used in the clinic. 100 A drawback is its low sensitivity: approximately micromolar concentrations of an imaging probe can be detected within a given voxel (10 À 3 -10 À 5 mol/l) which is three to six orders of magnitude lower than the sensitivity of optical imaging for detection of fluorochromes in vivo.…”

Section: Magnetic Resonance Imagingmentioning

confidence: 99%

“…100 A drawback is its low sensitivity: approximately micromolar concentrations of an imaging probe can be detected within a given voxel (10 À 3 -10 À 5 mol/l) which is three to six orders of magnitude lower than the sensitivity of optical imaging for detection of fluorochromes in vivo. 101 Benoit et al 102 exploited the innate physiology of magnetotactic bacteria to target tumors in mice and provide positive contrast for visualization using MRI.…”

Section: Magnetic Resonance Imagingmentioning

confidence: 99%

“…Nuclear medicine imaging modalities such as PET are highly sensitive but suffer from poor spatial resolution. 100 MRI has the highest image resolution, but sensitivity is less than nuclear techniques. 34 FP detection has shown some success at preclinical levels however high background levels and poor tissue penetration of both excitation and emission waves restrict efficacy.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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The significant burden of resistance to conventional anticancer treatments in patients with advanced disease has prompted the need to explore alternative therapeutic strategies. The challenge for oncology researchers is to identify a therapy which is selective for tumors with limited toxicity to normal tissue. Engineered bacteria have the unique potential to overcome traditional therapies' limitations by specifically targeting tumors. It has been shown that bacteria are naturally capable of homing to tumors when systemically administered resulting in high levels of replication locally, either external to (non-invasive species) or within tumor cells (pathogens). Pre-clinical and clinical investigations involving bacterial vectors require relevant means of monitoring vector trafficking and levels over time, and development of bacterial-specific real-time imaging modalities are key for successful development of clinical bacterial gene delivery. This review discusses the currently available imaging technologies and the progress to date exploiting these for monitoring of bacterial gene delivery in vivo.Cancer Gene Therapy ( INTRODUCTIONAlthough the potential anti-cancer effects of acquired bacterial infection have been evident for over 120 years and the presence of bacteria in excised tumors has been noted for over 60 years, 1 it is only in more recent times that the tumor-specific growth of bacteria has been considered for therapeutic purposes. While the precise mechanism(s) behind preferential bacterial tumor colonization remain poorly understood, this phenomenon must relate to unique tumor attributes that separate them from healthy tissues. Factors such as the irregular blood supply; local immune suppression; inflammation; and unique nutrient supply (e.g., purines) in tumors have been proposed to play a role. 2 Bacterial entry into the tumor environment is proposed to be facilitated by the leaky vasculature. Cancer cells are characterized by an aberrantly accelerated metabolism and proliferation leading to an imbalance of oxygen supply and consumption which is a major causative factor of tumor hypoxia. 3 The hypoxic nature of solid tumors enhances the growth of anaerobic and facultatively anaerobic bacteria. In addition, these areas with low oxygen and high interstitial pressure are considered to be an immunological sanctuary, where bacterial clearance mechanisms are greatly inhibited. 4 Necrotic regions are also rich in nutrients favoured by bacteria due to tumor cell turnover. However, tumor selective bacterial colonization now appears to be both bacterial species and tumor origin independent, since aerobic bacteria are also capable of colonising tumors, and even small tumors lacking an anaerobic center are colonised. See Figure 1 for proposed mechanisms.Invasive bacteria can internalize and replicate within tumor cells, while non-invasive bacteria grow externally to tumor cells, within the tumor micro-environment. 5 The tumor selective growth of bacteria has made them an attractive vehicle for the delivery of ...

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Section: Magnetic Resonance Imagingmentioning

confidence: 99%

Section: Magnetic Resonance Imagingmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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“…In addition, dilution of contrast agents and subsequent signal loss upon cell division would not be a concern. Although the use of reporter genes for BLI (for example, luciferases), for fluorescence imaging (for example, enhanced green fluorescent protein (eGFP)) and for PET (for example, HSV1-tk) is common practice (for an overview, see the studies by Deroose et al 2 and Waerzeggers et al 8 ), efforts are made to develop and validate gene-based contrast methods for MRI. [9][10][11][12][13] The genes proposed as 'pure' genetic MRI reporters, meaning that contrast generation is independent of (co-) substrate administration, are typically genes encoding proteins that sequester endogenous (super)paramagnetic ions.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the specificity and sensitivity of ferritin as an MRI reporter gene in the mouse brain using lentiviral and adeno-associated viral vectors

et al. 2011

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The development of in vivo imaging protocols to reliably track transplanted cells or to report on gene expression is critical for treatment monitoring in (pre)clinical cell and gene therapy protocols. Therefore, we evaluated the potential of lentiviral vectors (LVs) and adeno-associated viral vectors (AAVs) to express the magnetic resonance imaging (MRI) reporter gene ferritin in the rodent brain. First, we compared the induction of background MRI contrast for both vector systems in immune-deficient and immune-competent mice. LV injection resulted in hypointense (that is, dark) changes of T 2 /T 2 * (spin-spin relaxation time)-weighted MRI contrast at the injection site, which can be partially explained by an inflammatory response against the vector injection. In contrast to LVs, AAV injection resulted in reduced background contrast. Moreover, AAV-mediated ferritin overexpression resulted in significantly enhanced contrast to background on T 2 *-weighted MRI. Although sensitivity associated with the ferritin reporter remains modest, AAVs seem to be the most promising vector system for in vivo MRI reporter gene imaging. Gene Therapy (2011) INTRODUCTIONThe development of non-invasive imaging methods that can reliably report on therapeutic cell transplantation and/or gene expression is a critical step in the establishment of gene therapy protocols, both for clinical and for research applications. Several molecular imaging modalities are available that enable non-invasive and repeated imaging of gene expression in targeted cells in living organisms, thereby reducing the number of laboratory animals and reducing the inter-animal variability at the preclinical level. Among these are radionuclide imaging techniques such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), optical imaging methods including fluorescence imaging and bioluminescence imaging (BLI), magnetic resonance imaging (MRI) and spectroscopy, ultrasound and X-ray-based methods (for a review, see the studies by Massoud and Gambhir 1 and Deroose et al. 2 ). Apart from optical imaging methods, molecular imaging technologies using these imaging modalities have the advantage of being translatable to a clinical setting.When comparing imaging modalities, BLI, PET and SPECT provide high sensitivity but low resolution, whereas MRI can reach near-cellular resolution, 3-6 which makes MRI ideally suited to provide information on the location and migration of targeted cells in vivo.

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“…There is a growing awareness that assessment of location, magnitude and duration of transgene expression in vivo through various modern noninvasive imaging technologies may help develop efficient and safe gene therapy protocols. 3,4 Currently, the three most promising suicide gene/prodrug combinations are (1) herpes simplex virus thymidine kinase (HSV1-tk) with ganciclovir (GCV), 5 (2) CD (cytosine deaminase) from bacteria or yeast with 5-fluorocytidine 6,7 and (3) bacterial nitroreductase (NTR) with CB1954. 8 Of the three, HSV1-tk/GCV is at the forefront of gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

et al. 2011

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Gene-directed enzyme prodrug therapy (GDEPT) is a promising and emerging strategy that attempts to limit the systemic toxicity inherent to cancer chemotherapy by means of tumor-targeted delivery and expression of an exogenous gene whose product converts nontoxic prodrug(s) into activated cytotoxic agent(s). The bacterial nitroreductase (NTR) enzyme, coupled with its substrate prodrug 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), is a promising GDEPT strategy that has reached clinical trials. However, no strategy exists to visually monitor and quantitatively evaluate the therapeutic efficacy of NTR/CB1954 prodrug therapy in cells and imaging in living animals. As the success of any GDEPT is dependent upon the efficiency of transgene expression in vivo, we developed a safe, sensitive and reproducible noninvasive imaging method to monitor NTR transgene expression that would allow quantitative assessment of both therapeutic efficacy and diagnostic outcome of NTR/ CB1954 prodrug therapy in the future. Here, we investigate the use of a novel fluorescent imaging dye CytoCy5S (a Cy5-labeled quenched substrate of NTR enzyme) on various cancer cell lines in vitro and in NTR-transfected tumor-bearing animals in vivo. CytoCy5S-labeled cells become fluorescent at 'red-shifted' wavelengths (638 nm) when reduced by cellular NTR enzyme and remains trapped within the cells for extended periods of time. The conversion and entrapment was dynamically recorded using a time-lapsed microscopy. Systemic and intratumoral delivery of CytoCy5S to NTR-expressing tumors in animals indicated steady and reproducible signals even 16 h after delivery (Po0.001). This is the first study to address visual monitoring and quantitative evaluation of NTR activity in small animals using CytoCy5S, and establishes the capability of NTR to function as an imageable reporter gene.

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Methods to monitor gene therapy with molecular imaging

Cited by 63 publications

References 140 publications

Bacterial vectors for imaging and cancer gene therapy: a review

Bacterial vectors for imaging and cancer gene therapy: a review

Evaluation of the specificity and sensitivity of ferritin as an MRI reporter gene in the mouse brain using lentiviral and adeno-associated viral vectors

Noninvasive optical imaging of nitroreductase gene-directed enzyme prodrug therapy system in living animals

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