Preclinical Evaluation of Gene Therapy for NF2 Lesions in Mouse Models Using Amplicon Vectors and Prodrug Activation.

摘要

Spontaneous schwannomas were detected in a transgenic murine model of NF2 by Magnetic Resonance imaging (MRI). rumors were detected in the central and peripheral nervous system, in smooth muscles of the uterus and limbs, and in the intercostals muscles of adult mice These tumors display isointensity with other organs following T1 weighted image sequences and hyperintensity following T2- weighted image sequences, which are characteristic features of schwannomas in humans Hematoxylin and Eosin (H and E) staining and immunohistochemistry indicate that these tumors consist of schwannomas and Schwann cell hyperplasias. Tumors stain positively for 8.100, a marker for cells of Schwann cell origin, and VSV-i, a marker for the mutated NF2 transgene placed under the control of the Schwann cell-specific PO promoter. Preliminary evidence suggests that these tumors are highly infectable with the replicational-conditional virus HSV vector, hrR3, which contains the reporter gene, lacZ. In addition, we have been successful in producing meningiomas in the ventricles and brain parenchyma of immunodeficient mice by injection of a malignant human meningioma cell line, F5, into the ventricles. This cell line also appears to highly infectable with HSV vectors. Thus, two NF2 tumor models have been established in mice appropriate for testing of therapeutic HSV vectors.