Imaging-Guided Gene Therapy of Experimental Gliomas

Jacobs, Andréas H.; Rueger, Maria Adele; Winkeler, Alexandra; Li, Hong Feng; Vollmar, Stefan; Waerzeggers, Yannic; Rueckriem, Benedict; Kummer, Christiane; Dittmar, Claus; Klein, Markus; Heneka, Michael T.; Herrlinger, Ulrich; Fraefel, Cornel; Graf, Rudolf; Wienhard, K.; Heiss, Wolf‐Dieter

doi:10.1158/0008-5472.can-06-2418

Cited by 54 publications

(44 citation statements)

References 53 publications

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“…The expression of HSV-1-tk, which selectively incorporates certain radiolabeled nucleoside analogues into DNA (26 -28), can be noninvasively imaged in distinct regions of a transduced tissue (19, 21, 23, 26, 29 -34). In particular, HSV-1-tk -based PET imaging has been used to evaluate the transduction efficiency of viral vectormediated gene therapy in various applications in vivo (19,21,35,36). We extended this approach using PET and MRI techniques to a complete therapeutic follow-up with terminal histology.…”

Section: Discussionmentioning

confidence: 99%

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Normal Brain Cells Contribute to the Bystander Effect in Suicide Gene Therapy of Malignant Glioma

Miletić

Fischer

Giroglou

et al. 2007

Clinical Cancer Research

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Purpose: Lentiviral vectors pseudotyped with glycoproteins of the lymphocytic choriomeningitis virus (LCMV-GP) are promising candidates for gene therapy of malignant glioma, as they specifically and efficiently transduce glioma cells in vitro and invivo. Here, we evaluated the therapeutic efficacy of LCMV-GP and vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors. Experimental Design: Therapeutic efficacy was tested for unmodified (9L) and DsRedmodified (9LDsRed) gliomas using the suicide gene thymidine kinase of the herpes simplex virus type 1 (HSV-1-tk). Positron emission tomography (PET) and magnetic resonance imaging were done to analyze transduction of tumors and monitor therapeutic outcome. Results: LCMV-GP pseudotypes mediated a successful eradication of 9LDsRed tumors with 100% of long-term survivors. Before initiation of ganciclovir treatment, a strong HSV-1-tk expression within the tumor was detected by noninvasive PET using the tracer 9-[4-[18 F]fluoro-3-(hydroxymethyl)butyl]guanine.Therapeutic outcome was successfully monitored by magnetic resonance imaging and PET imaging and correlated with the histopathologic data. In the 9L model, LCMV-GP and VSV-G pseudotyped lentiviral vectors displayed similar therapeutic efficacy. Further studies revealed that normal brain cells transduced with VSV-G pseudotypes were not eliminated by ganciclovir treatment and contributed significantly to the bystander killing of tumor cells. Conclusions: Suicide gene transfer using pseudotyped lentiviral vectors was very effective in the treatment of rat glioma and therefore is an attractive therapeutic strategy also in human glioblastoma especially in conjunction with an imaging-guided approach. In addition, high selectivity of gene transfer to tumor cells may not always be desirable for therapeutic genes that exert a clear bystander effect.

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Section: Discussionmentioning

confidence: 99%

“…(tail vein) into experimental animals with the following doses: no-carrier-added Localization of tumor before and during gene therapy was done by MRI and [ 11 C]MET PET. The respective PET images were coregistered to MR images as described (19,21).…”

Section: Methodsmentioning

confidence: 99%

Normal Brain Cells Contribute to the Bystander Effect in Suicide Gene Therapy of Malignant Glioma

Miletić

Fischer

Giroglou

et al. 2007

Clinical Cancer Research

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“…Extensive studies in neurooncology have established the radiotracer 3'-deoxy-3'-[ [69][70][71][72] . [ 18 F]FLT is a thymidine analogue that is incorporated into the DNA of dividing cells-similar to bromodeoxyuridine (BrdU) well established for their immunohistochemical detection-where it is irreversibly trapped, its positron-emitting properties allowing for its non-invasive detection [73] .…”

Section: Imaging Endogenous Neural Stem Cells In Vivomentioning

confidence: 99%

In vivoimaging of endogenous neural stem cells in the adult brain

Rueger

Schroeter

2015

WJSC

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The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their ability to self-renew and differentiate into functional neurons, astrocytes and oligodendrocytes has raised the hope for novel therapies of neurological diseases. Experimentally, those eNSCs can be mobilized in vivo , enhancing regeneration and accelerating functional recovery after, e.g., focal cerebral ischemia, thus constituting a most promising approach in stem cell research. In order to translate those current experimental approaches into a clinical setting in the future, non-invasive imaging methods are required to monitor eNSC activation in a longitudinal and intraindividual manner. As yet, imaging protocols to assess eNSC mobilization non-invasively in the live brain remain scarce, but considerable progress has been made in this field in recent years. This review summarizes and discusses the current imaging modalities suitable to monitor eNSCs in individual experimental animals over time, including optical imaging, magnetic resonance tomography and-spectroscopy, as well as positron emission tomography (PET). Special emphasis is put on the potential of each imaging method for a possible clinical translation, and on the specificity of the signal obtained. PET-imaging with the radiotracer 3'-deoxy-3'-[18 F]fluoro-L-thymidine in particular constitutes a modality with excellent potential for clinical translation but low specificity; however, concomitant imaging of neuroinflammation is feasible and increases its specificity. The non-invasive imaging strategies presented here allow for the exploitation of novel treatment strategies based upon the regenerative potential of eNSCs, and will help to facilitate a translation into the clinical setting.

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“…18 F]FLT was synthesized by nucleophilic substitution using benzoyl-protected anhydrothymidine according to the method of Machulla et al (2000), with minor modifications, and as described previously (Jacobs et al, 2007). The synthesis was carried out using an automated synthesis module (Nuclear Interface).…”

Section: Radiochemistry [mentioning

confidence: 99%

Noninvasive Imaging of Endogenous Neural Stem Cell MobilizationIn VivoUsing Positron Emission Tomography

Rueger¹,

Backes²,

Walberer³

et al. 2010

J. Neurosci.

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Neural stem cells reside in two major niches in the adult brain [i.e., the subventricular zone (SVZ) and the dentate gyrus of the hippocampus]. Insults to the brain such as cerebral ischemia result in a physiological mobilization of endogenous neural stem cells. Since recent studies showed that pharmacological stimulation can be used to expand the endogenous neural stem cell niche, hope has been raised to enhance the brain's own regenerative capacity. For the evaluation of such novel therapeutic approaches, longitudinal and intraindividual monitoring of the endogenous neural stem cell niche would be required. However, to date no conclusive imaging technique has been established. We used positron emission tomography (PET) and the radiotracer 3Ј-deoxy-3Ј-[

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Imaging-Guided Gene Therapy of Experimental Gliomas

Cited by 54 publications

References 53 publications

Normal Brain Cells Contribute to the Bystander Effect in Suicide Gene Therapy of Malignant Glioma

Normal Brain Cells Contribute to the Bystander Effect in Suicide Gene Therapy of Malignant Glioma

In vivoimaging of endogenous neural stem cells in the adult brain

Noninvasive Imaging of Endogenous Neural Stem Cell MobilizationIn VivoUsing Positron Emission Tomography

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