Treatment of schwannomas with an oncolytic recombinant herpes simplex virus in murine models of neurofibromatosis type 2.
Gene therapy for schwannomas was evaluated in two mouse models of neurofibromatosis type 2 (NF2): (1) a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas, and (2) a xenograft model in which human schwannoma tissue is implanted subcutaneously into immune- compromised mice. In both models, schwannoma volumes were monitored by magnetic resonance imaging (MRI) and showed strong gadolinium enhancement typical of these tumors in humans. Both types of tumor were positive for the Schwann cell marker S100, and highly infectable with herpes simplex virus (HSV) vectors. Schwannomas were injected with an oncolytic HSV-1 recombinant virus vector, G47Delta, which has deletions in genes for ribonucleotide reductase (ICP6), gamma34.5, and ICP47. In the NF2 transgenic model, schwannomas were reduced by more than half their original size by 10 days after infection. In the case of subcutaneous schwannoma xenografts, reduction in size after infection occurred more slowly, with a mean reduction of onethird by 42 days after treatment. Schwannomas injected with control vehicles continued to grow slowly over time in both schwannoma models. These studies demonstrate the ability of an oncolytic recombinant HSV vector to reduce the volume of schwannoma tumors in NF2 tumor models in mice and extend the possible therapeutic applications of oncolytic vectors for benign tumors to reduce mass while minimizing nerve damage.
Messerli
Shanta M
SM
Molecular Neurogenetics Unit, Department of Neurology, Harvard Medical School, and Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Prabhakar
Shilpa
S
Tang
Yi
Y
Mahmood
Umar
U
Giovannini
Marco
M
Weissleder
Ralph
R
Bronson
Rodrick
R
Martuza
Robert
R
Rabkin
Samuel
S
Breakefield
Xandra O
XO
D000818:Animals; D016543:Central Nervous System Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D004274:DNA, Recombinant / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology / Q000633:toxicity; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009442:Neurilemmoma / Q000145:classification / Q000473:pathology / Q000628:therapy* / Q000821:virology; D016518:Neurofibromatosis 2 / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*
D004274:DNA, Recombinant