Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo

• Published in: Gene therapy Vol. 16; no. 2; pp. 262 - 278
• Main Authors: Tyler, M A, Ulasov, I V, Sonabend, A M, Nandi, S, Han, Y, Marler, S, Roth, J, Lesniak, M S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2009; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brain cancer; Brain Neoplasms - therapy; Brain Neoplasms - virology; Brain tumors; Care and treatment; Cell Biology; Cell Movement - physiology; Central nervous system; Clinical trials; Expression vectors; Flow cytometry; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene transfer; Genetic aspects; Genetic vectors; Genetic Vectors - genetics; Genetic Vectors - pharmacokinetics; Glioma; Glioma - therapy; Glioma - virology; Glioma cells; Gliomas; Health aspects; Health. Pharmaceutical industry; Human Genetics; Humans; Immunotherapy; Industrial applications and implications. Economical aspects; Inhibitor of Apoptosis Proteins; Male; Medical sciences; Mice; Mice, Nude; Microtubule-Associated Proteins - biosynthesis; Microtubule-Associated Proteins - genetics; Nanotechnology; Neoplasm Transplantation; Nervous system; Neural stem cells; Neurons - virology; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - physiology; Original; original-article; Receptors, CXCR4 - biosynthesis; Receptors, CXCR4 - genetics; Replication; RNA, Messenger - genetics; Stem Cell Transplantation - methods; Stem cells; Stem Cells - virology; Survivin; Transcription, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor cells; Tumor Cells, Cultured; Virus Replication; Viruses; United States; glioma; brain tumor; virotherapy; neural stem cells; oncolytic virus; adenovirus; Intracranial; Nervous system diseases; Adenoviridae; Stem cell; Intracranial tumor; Cerebral disorder; Virus; In vivo; Glioma; Central nervous system disease; Target cell; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2008.165

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.