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Small Animal PET Imaging of hTERT RNA-Targeted HSV1-tk Gene Expression with Trans-Splicing Ribozyme
Min-Jung Seo1, Ju Hui Park1, Kyo Chul Lee1
1Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Abstract:
Trans-splicing ribozymes (TSR) are useful anticancer agents targeting cancer-specific transcripts and replacing the RNA to induce anticancer gene expression specifically and selectively in cancer cells. Similar to other gene therapy methods, it is also important to evaluate the transgene expression for target specificity and ribozyme activity. In this study, the authors performed in vivo small animal positron emission tomography (PET) imaging and biodistribution assay to evaluate human telomerase reverse transcriptase (hTERT) RNA-targeting-specific TSR, which directs the expression of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene selectively in hTERT-positive tumors through targeted RNA replacement of the hTERT transcript. The hTERT RNA-targeted HSV1-tk expression with TSR was monitored by PET imaging with 124I labeled 2'-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-iodouracil, which is one of the thymidine derivatives acting as substrates for HSV1-tk, in hTERT-positive tumor-bearing mice. Imaging of hTERT RNA-targeted HSV1-tk expression by TSR could be used in the development of advanced gene therapy using tumor-specific TSR.
Insights
Trans-splicing ribozymes (TSR) show promise for cancer gene therapy by targeting cancer-specific RNA. This study used PET imaging to successfully monitor TSR-mediated gene expression in tumors, validating its potential for targeted cancer treatment.
Area of Science:
- Molecular Biology
- Gene Therapy
- Oncology
Background:
- Trans-splicing ribozymes (TSR) offer targeted gene therapy by replacing cancer-specific RNA transcripts.
- Evaluating transgene expression and ribozyme activity is crucial for gene therapy efficacy.
- Human telomerase reverse transcriptase (hTERT) is a cancer-specific target suitable for RNA-based therapies.
Purpose of the Study:
- To evaluate the in vivo performance of an hTERT RNA-targeting TSR.
- To assess the specificity and activity of TSR-mediated gene expression in hTERT-positive tumors.
- To demonstrate the utility of PET imaging for monitoring TSR-based gene therapy.
Main Methods:
- Developed an hTERT RNA-targeting TSR to express herpes simplex virus type 1 thymidine kinase (HSV1-tk).
- Utilized in vivo small animal positron emission tomography (PET) imaging.
- Administered a radiolabeled thymidine analog (124I-FLT) as a substrate for HSV1-tk.
Main Results:
- PET imaging successfully visualized HSV1-tk expression specifically in hTERT-positive tumors.
- Biodistribution assays confirmed the targeted delivery and expression of the therapeutic gene.
- The study demonstrated the feasibility of monitoring TSR activity in real-time.
Conclusions:
- hTERT RNA-targeting TSR can selectively direct gene expression in cancer cells.
- PET imaging is a valuable tool for evaluating the efficacy and specificity of TSR-based gene therapies.
- This approach holds potential for developing advanced, tumor-specific gene therapies.
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