title: Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells.
abstract: There are currently no satisfactory treatments or experimental models showing autonomic dysfunction for intramedullary spinal cord gliomas (ISCG).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: ‡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.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Ropper
authors.forename: Xiang
authors.initials: X
authors.lastname: Zeng
authors.forename: Hariprakash
authors.initials: H
authors.lastname: Haragopal
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Anderson
authors.forename: Zaid
authors.initials: Z
authors.lastname: Aljuboori
authors.forename: Inbo
authors.initials: I
authors.lastname: Han
authors.forename: Muhammad
authors.initials: M
authors.lastname: Abd-El-Barr
authors.forename: Hong Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Snyder
authors.forename: Mariano S
authors.initials: MS
authors.lastname: Viapiano
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: John H
authors.initials: JH
authors.lastname: Chi
authors.forename: Yang D
authors.initials: YD
authors.lastname: Teng
mesh_terms: D000818:Animals; D043525:Cytosine Deaminase / Q000235:genetics; D005437:Flucytosine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D015774:Ganciclovir / Q000008:administration & dosage / Q000031:analogs & derivatives; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D006801:Humans; D058953:Neural Stem Cells / Q000637:transplantation*; D051381:Rats; D013120:Spinal Cord Neoplasms / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods*; D013937:Thymidine Kinase / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C092309:ganciclovir triphosphate; D005437:Flucytosine; D013937:Thymidine Kinase; D043525:Cytosine Deaminase; D015774:Ganciclovir; D005472:Fluorouracil