M. Maher Hulou and E. Antonio Chiocca
Gordon Tang and E. Antonio Chiocca
Gene transfer offers the potential to explore basic physiological processes and to intervene in human disease. The central nervous system (CNS) presents a fertile field in which to develop novel therapeutic modalities to treat intractable and pervasive malignant tumors and neurodegenerative disease. The extension of gene therapy to the CNS, however, faces the delivery obstacles of a target population that is postmitotic and isolated behind a blood-brain barrier (BBB). Approaches to this problem have included grafting of genetically modified cells to deliver novel proteins or introducing genes by viral or synthetic vectors geared toward the CNS cell population. Direct inoculation and bulk flow, as well as osmotic and pharmacological disruption, have been used to circumvent the BBB's exclusionary role. Once the gene is delivered, myriad strategies have been used to affect a therapeutic result. Genes activating prodrugs are the most common antitumor approach. Other approaches focus on activating immune responses, targeting angiogenesis, and influencing apoptosis and tumor suppression. At this time, therapy directed at neurodegenerative diseases has centered on ex vivo gene therapy for supply of trophic factors to promote neuronal survival, axonal outgrowth, and target tissue function. Despite early promise, gene therapy for CNS disorders will require advancements in methods for delivery and long-term expression before becoming feasible for human disease.
Bob S. Carter and E. Antonio Chiocca
James P. Basilion, Tomotsuga Ichikawa and E. Antonio Chiocca
The explosion of molecular techniques for gene discovery and their application to a variety of diseases has uncovered numerous gene abnormalities that can result in disease. These discoveries have provided the needed understanding and genetic materials to apply gene therapy approaches in the treatment of several diseases, including those of the central nervous system. A variety of different anticancer complementary DNAs (cDNA) have been shown to possess biological efficacy when used in the appropriate experimental setting. However, efficient and effective delivery of these cDNAs remains a major obstacle for future clinical applications. The focus of this review will be to describe the obstacles that impede the process of gene therapy and oncolytic viral therapy of brain tumors and to describe how important new discoveries derived from other disciplines are being used to address problems encountered in the gene/ viral therapy of this disease.
Neurosurgical “pearls” and neurosurgical evidence
E. Antonio Chiocca
Daniel Ikeda and E. Antonio Chiocca
E. Antonio Chiocca
Massive growth of a meningioma into the brachial plexus and thoracic cavity after intraspinal and supraclavicular resection
Case report and review of the literature
Edward R. Smith, Mark Ott, John Wain, David N. Louis and E. Antonio Chiocca
✓ Extracranial meningiomas comprise approximately 2% of all meningiomas. Involvement of peripheral nerves by meningioma, either by a primary tumor or through secondary extension of an intraaxial lesion, is a much rarer entity; there have been only two reported primary brachial plexus meningiomas and one description of secondary involvement of the brachial plexus by extension of an intraaxial lesion. Although thoracic cavity meningiomas have been described in the literature, their pathogenesis is poorly understood. The authors present the case report of a 36-year-old man who was initially treated for a thoracic spinal meningioma that infiltrated the brachial plexus. After resection, progressive and massive growth with infiltration of the brachial plexus and pleural cavity occurred over a 5-year period despite radio- and chemotherapy. The case report is followed by a review of the literature of this rare entity.
Keiro Ikeda, Yoshinaga Saeki, Charo Gonzalez-Agosti, Vijaya Ramesh and E. Antonio Chiocca
Object. The absence of in vitro models of neurofibromatosis Type 2 (NF2)—defective meningiomas has limited investigative efforts to study the biological effects of this gene in the pathogenesis of these tumors. The goals of this report are to show that gene transfer vectors can efficiently express the wild-type NF2 transgene into primary meningioma cells and to determine effects on cellular proliferation.
Methods. In this study, the authors have compared the transducing capacities of a retrovirus, an adenovirus, and a herpes simplex virus amplicon vector for use in primary human meningioma cells harvested from human tumors excised from patients with and without NF2. Transduction efficiencies with the latter vector approached 100% and it was selected to transfer the wild-type NF2 transgene into these cells. Western blot analysis confirmed that vector-mediated gene transfer mediated the expression of the NF2-encoded polypeptide merlin. Overexpression of merlin significantly inhibited the proliferation of both NF2-negative and NF2-positive human meningioma cells when compared to the proliferation of cells transduced with a control vector.
Conclusions. This study demonstrates the feasibility of using vector-mediated gene transfer to study wild-type NF2 gene function in short-term cultures of primary human meningioma cells.
Jung Kyo Lee, Benjamin Choi, Raymond A. Sobel, E. Antonio Chiocca and Robert L. Martuza
✓ A human neurofibrosarcoma was removed at surgery from a patient with neurofibromatosis and implanted into the subrenal capsule of female nude mice (nu/nu). A solid tumor grew and was transferred to 78 additional mice for this study. The animals were randomly assigned to one of four groups: 1) control, 27 animals; 2) oral heparin (200 or 500 U/ml), 17 animals; 3) oral hydrocortisone (0.3 mg/ml), 10 animals; or 4) oral heparin (200, 500, or 1000 U/ml) with hydrocortisone (0.3 mg/ml), 24 animals. After 10 days of treatment, the animals were sacrificed and the tumor size and degree of neovascularization were compared to the pretreatment data. Heparin treatment alone stimulated angiogenesis and resulted in tumor growth greater than in the control group (p < 0.001). Administration of hydrocortisone alone caused a minimal reduction in tumor growth and had a minimal effect on angiogenesis (p < 0.05 vs. control group). In contrast, heparin administered with hydrocortisone inhibited both angiogenesis and tumor growth (p < 0.001 vs. control group). These studies suggest that angiogenesis modulators are worthy of further study as a feasible means of treating human neurofibrosarcoma.