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Published on: June 4, 2017
Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells
Alexander E Ropper1, Xiang Zeng, Hariprakash Haragopal
1‡Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; §Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, Massachusetts; ¶Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea; ‖Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; #Stem Cell Center, Sanford-Burnham Medical Research Institute, La Jolla, California; **Department of Medicine, University of British Columbia, Vancouver, BC, Canada; ‡‡Department of PM&R, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts.
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.
