Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells. Issue 3 (September 2016)

• Record Type: Journal Article
• Authors: Ropper, Alexander E.; Zeng, Xiang; Haragopal, Hariprakash; Anderson, Jamie E.; Aljuboori, Zaid; Han, Inbo; Abd-El-Barr, Muhammad; Lee, Hong Jun; Sidman, Richard L.; Snyder, Evan Y.; Viapiano, Mariano S.; Kim, Seung U.; Chi, John H.; Teng, Yang D.
• Is Part Of: Neurosurgery. Volume 79:Issue 3(2016)
• Publication Date: 2016-09
• Subjects: Autonomic dysfunction -- Genetic engineering -- Glioma -- Neural stem cells -- Spinal cord tumor -- Targeted therapy; Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/NEU.0000000000001174
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : BACKGROUND: There are currently no satisfactory treatments or experimental models showing autonomic dysfunction for intramedullary spinal cord gliomas (ISCG). OBJECTIVE: To develop a rat model of ISCG and investigate whether genetically engineered human neural stem cells (F3.hNSCs) could be developed into effective therapies for ISCG. METHODS: Immunodeficient/Rowett Nude rats received C6 implantation of G55 human glioblastoma cells (10K/each). F3.hNSCs engineered to express either cytosine deaminase gene only (i.e., F3.CD) or dual genes of CD and thymidine kinase (i.e., F3.CD-TK) converted benign 5-fluorocytosine and ganciclovir into oncolytic 5-fluorouracil and ganciclovir-triphosphate, respectively. ISCG rats received injection of F3.CD-TK, F3.CD, or F3.CD-TK debris near the tumor epicenter 7 days after G55 seeding, followed with 5-FC (500 mg/kg/5 mL) and ganciclovir administrations (25 mg/kg/1 mL/day × 5/each repeat, intraperitoneal injection). Per humane standards for animals, loss of weight-bearing stepping in the hindlimb was used to determine post-tumor survival. Also evaluated were autonomic functions and tumor growth rate in vivo. RESULTS: ISCG rats with F3.CD-TK treatment survived significantly longer (37.5 ± 4.78 days) than those receiving F3.CD (21.5 ± 1.75 days) or F3.CD-TK debris (19.3 ± 0.85 days; n = 4/group; P < .05, median rank test), with significantly improved autonomic function and reduced tumor growth rate. F3.DC-TK cells migrated diffusively into ISCG clusters to mediate oncolytic effect. CONCLUSION: Dual gene-engineered human neural stem cell regimen markedly prolonged survival in a rat model that emulates somatomotor and autonomic dysfunctions of human cervical ISCG. F3.CD-TK may provide a novel approach to treating clinical ISCG. ABBREVIATIONS: 5FC, 5-fluorocytosine BBB, Basso, Beattie, and Bresnahan CD, cytosine deaminase DP, diastolic blood pressure GCV, ganciclovir; hNSCs, human neural stem cells ISCG, intramedullary spinal cord gliomas MAP, mean arterial blood pressure NSCs, neural stem cells SP, systolic blood pressure TK, thymidine kinase Abstract : Supplemental Digital Content is Available in the Text.