Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells.

Journal Article (Journal Article)

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-fluorocytosineBBB, Basso, Beattie, and BresnahanCD, cytosine deaminaseDP, diastolic blood pressureGCV, ganciclovir; hNSCs, human neural stem cellsISCG, intramedullary spinal cord gliomasMAP, mean arterial blood pressureNSCs, neural stem cellsSP, systolic blood pressureTK, thymidine kinase.

Full Text

Duke Authors

Cited Authors

  • Ropper, AE; Zeng, X; Haragopal, H; Anderson, JE; Aljuboori, Z; Han, I; Abd-El-Barr, M; Lee, HJ; Sidman, RL; Snyder, EY; Viapiano, MS; Kim, SU; Chi, JH; Teng, YD

Published Date

  • September 2016

Published In

Volume / Issue

  • 79 / 3

Start / End Page

  • 481 - 491

PubMed ID

  • 26671631

Electronic International Standard Serial Number (EISSN)

  • 1524-4040

International Standard Serial Number (ISSN)

  • 0148-396X

Digital Object Identifier (DOI)

  • 10.1227/neu.0000000000001174

Language

  • eng