Gene therapy of experimental brain tumors using neural progenitor cells.
Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.
Benedetti
S
S
Istituto Nazionale Neurologico Besta, via Celoria 11, 20133 Milano, Italy.
Pirola
B
B
Pollo
B
B
Magrassi
L
L
Bruzzone
M G
MG
Rigamonti
D
D
Galli
R
R
Selleri
S
S
Di Meco
F
F
De Fraja
C
C
Vescovi
A
A
Cattaneo
E
E
Finocchiaro
G
G
D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002540:Cerebral Cortex / Q000166:cytology; D015316:Genetic Therapy; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015847:Interleukin-4