Abstract
Adenoviral oncolytic virotherapy represents an attractive treatment modality for central nervous system (CNS) neoplasms. However, successful application of virotherapy in clinical trials has been hampered by inadequate distribution of oncolytic vectors. Neural stem cells (NSCs) have been shown as suitable vehicles for gene delivery because they track tumor foci. In this study, we evaluated the capability of NSCs to deliver a conditionally replicating adenovirus (CRAd) to glioma. We examined NSC specificity with respect to viral transduction, migration and capacity to deliver a CRAd to tumor cells. Fluorescence-activated cell sorter (FACS) analysis of NSC shows that these cells express a variety of surface receptors that make them amenable to entry by recombinant adenoviruses. Luciferase assays with replication-deficient vectors possessing a variety of transductional modifications targeted to these receptors confirm these results. Real-time PCR analysis of the replication profiles of different CRAds in NSCs and a representative glioma cell line, U87MG, identified the CRAd-Survivin (S)-pk7 virus as optimal vector for further delivery studies. Using in vitro and in vivo migration studies, we show that NSCs infected with CRAd-S-pk7 virus migrate and preferentially deliver CRAd to U87MG glioma. These results suggest that NSCs mediate an enhanced intratumoral distribution of an oncolytic vector in malignant glioma when compared with virus injection alone.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 262-278 |
| Number of pages | 17 |
| Journal | Gene therapy |
| Volume | 16 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2009 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by the National Cancer Institute (R01-CA122930), the National Institute of Neurological Disorders and Stroke (K08-NS046430), The Alliance for Cancer Gene Therapy Young Investigator Award and the American Cancer Society (RSG-07-276-01-MGO). We are grateful for the assistance of Dr Dingcai Cao, a biostatistician at the University of Chicago, in preparing this article. We also acknowledge Dr Vytas Bindokas and Shirley Bond (University of Chicago Integrated Microscopy Research Facility) for their help in obtaining the fluorescent microscope images presented in this article.