Schwannomas and meningiomas are tumors that form in neurofibromatosis type 2 (NF2) patients by overgrowth of cells that support neurons in the nervous system. Although these tumors are generally not malignant, they can infringe on normal functions of the nervous system causing pain, paralysis, seizures, hearing loss, and death. These types of tumors, which grow slowly and usually remain localized to the area of origin, are well suited for gene therapy in its present state of development.

The goal of this application is to develop safe, targeted gene delivery methods to treat and evaluate responses in Schwannomas and meningiomas in mouse models of NF2, as a step toward clinical therapy. We have shown that spontaneous Schwannomas in a transgenic mouse model of NF2 and implanted meningiomas can be monitored in living mice using magnetic resonance imaging (MRI), and these tumors are highly infectable with vectors derived from herpes simplex virus (HSV) type 1. Imaging methods also will be used to evaluate tumor growth by detecting the light emitted by firefly luciferase expressed in tumor cells. To visualize cell death during treatment, we will use a novel fluorescent probe that is activated by proteins expressed in apoptotic dying cells. This unique ability to track Schwannomas and meningiomas in living mice with noninvasive imaging methods will allow targeting of injections, assessment of gene delivery, and monitoring of size changes in tumors in response to therapeutic interventions.

Several types of therapeutic HSV vectors will be tested. One vector will consist of the HSV particle containing DNA for expression of proteins that cause cell death. Schwannoma tumor cells will be targeted by placing expression of these proteins under the control of a promoter that is only active in Schwann cells, as well as by direct injection into the tumor. The other vector will consist of HSV altered to preferentially propagate in tumor cells, with propagation leading to cell death. Both these vectors are compatible with clinical trials. Our goal is to compare the ability of these vectors to reduce tumor growth/mass in a manner that is nontoxic to normal tissues, thus allowing treatment of tumors not curable with surgery and avoiding debilitating, invasive, and painful surgical methods to remove tumor masses. This proposal brings together a multidisciplinary group of investigators, both clinical and basic, with a long-standing interest in neurofibromatosis, tumors of the nervous system, and gene therapy to develop a new strategy for treating tumors arising in NF2 that can be applied in the clinic.