title: Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1.
abstract: Schwannomas are tumors formed by proliferation of dedifferentiated Schwann cells. Patients with neurofibromatosis 2 (NF2) and schwannomatosis develop multiple schwannomas in peripheral and cranial nerves. Although benign, these tumors can cause extreme pain and compromise sensory/motor functions, including hearing and vision. At present, surgical resection is the main treatment modality, but it can be problematic because of tumor inaccessibility and risk of nerve damage. We have explored gene therapy for schwannomas, using a model in which immortalized human NF2 schwannoma cells expressing a fluorescent protein and luciferase are implanted in the sciatic nerve of nude mice. Direct injection of an adeno-associated virus (AAV) serotype 1 vector encoding caspase-1 (ICE) under the Schwann-cell specific promoter, P0, leads to regression of these tumors with essentially no vector-mediated neuropathology, and no changes in sensory or motor function. In a related NF2 xenograft model designed to cause measurable pain behavior, the same gene therapy leads to tumor regression and concordant resolution of tumor-associated pain. This AAV1-P0-ICE vector holds promise for clinical treatment of schwannomas by direct intratumoral injection to achieve reduction in tumor size and normalization of neuronal function.
authors.affiliation: Neuroscience Center, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Mehran
authors.initials: M
authors.lastname: Taherian
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.forename: Jillian
authors.initials: J
authors.lastname: Brockmann
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Brenner
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009442:Neurilemmoma / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy*; D016518:Neurofibromatosis 2 / Q000473:pathology / Q000628:therapy; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011597:Psychomotor Performance; D012583:Schwann Cells / Q000473:pathology*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D020170:Caspase 1