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

摘要

These studies were designed to characterize tumors in mouse models of NF2 and to evaluate vector mediated therapy. Magnetic resonance, bioluminescence and near-infrared imaging were used in monitoring changes in tumor volume and in tracking gene delivery to there lesions over time in living animals. Several mouse models for NF2 were tested including: transgenic mice which express a dominant mutant form of the NF2 protein and develop spontaneous schwannomas; induction of schwannomas and brain tumors by injection of HSV amplicon vectors expressing Cre recombinase into mice homozygous for a floxed NF2 gene; and implantation of humanschwannoma or meningioma tissue into nude mice. Both schwannomas and meningiomas were shown to be highly infectable with therapeutic vectors derived from herpes simplex virus type-l. Injection of an oncolytic HSV vector G47A into schwannomas of transgenic mice led to a reproducible reduction in tumor volume. An HSV amplicon vector expressing the apostolic protein, caspase-11 was also developed. These vectors can potentially be used to reduce volume of surgically inaccessible tumors in NF2 patients.