Gene Therapy for Neurofibromatosis Type 2 Tumors

Our research involves evaluating gene therapy for schwannomas and meningiomas in murine models of Neurofibromatosis Type 2 (NF2).  The mouse models consist of a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas by 18 months of age and xenograft implantation models in which human schwannoma or meningioma tissue are implanted subcutaneously into the flanks of  immunodeficient mice. Currently, we are evaluating the effect on tumor growth of an oncolytic HSV-1 recombinant virus vector, G47D, which replicates only in dividing cells, has reduced neurovirulence, causes enhanced presentation of MHC Class I on the plasma membrane, and stimulates infiltrating lymphocytes.  MRI is used both to localize tumors and to quantitate tumor volume over time in vivo.  Injection of G47D into subcutaneous schwannomas in NF2 transgenic mice reduces mass over subsequent weeks, while tumors in the same animal injected with a control vector continued to grow (Figure 1, n=5).  Tumor reduction has been observed in both the transgenic model for NF2 and the human schwannoma and meningioma xenograft models following infection withG47D.  Animals are sacrificed for correlative histochemistry and immunocytochemistry to assess gene delivery and pathology.  We are also developing strategies to target apoptosis-inducing HSV amplicon vectors specifically to schwannoma or meningioma tissue using promoters specific to Schwann cells or meningioma tissue. By using preclinical NF2 tumor murine models, our studies will provide insight into possible therapeutic HSV treatment modalities which could potentially be used for other types of cancer as well.