Molecular Neurosurgery Laboratory
Samuel David Rabkin, PhD

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HomePage@Neurosurgery Office PPD Information Harvard Information Molecular Neurosurgery Laboratory Richard B. Simches Research Center, Brain Tumor Research Center, Massachusetts General Hospital CPZN-3-3800 617-726-6817 (Phone) 617-643-3422 (Fax) Post-docs: 3 Completed PhDs: 2 Telephone: 617-726-6817 Fax: 617-726-5677 Email: rabkin@helix.mgh.harvard.edu Rabkin Publications Rabkin Pubs 2007 Rabkin Pubs 2006 Rabkin Pubs 2005 Rabkin Pubs 2004 Rabkin Pubs 2003 Rabkin Pubs 2002 Rabkin Pubs 2001 Rabkin Pubs 2000 Rabkin Pubs 1999

Major Research Interest - Gene Therapy

Use of herpes simplex virus (HSV) vectors for cancer therapy and gene delivery to the nervous system

Research Summary

Dr. Rabkin is Associate Professor of Surgery (Microbiology and Molecular Genetics) at Harvard Medical School and Associate Virologist in Neurosurgery at Massachusetts General Hospital, Boston. He received his B.Sc. degree from the University of Toronto, his M.Sc. degree from the Hebrew University of Jerusalem and his Ph.D. degree from the University of Chicago. His postdoctoral work was done at Harvard Medical School.

Research in this laboratory focuses on the use of herpes simplex virus (HSV) vectors for cancer therapy and gene delivery in the nervous system, with the long-term goal being the therapeutic application of these vectors to patients. Gene therapy is a rapidly evolving field with enormous clinical potential. The vectors also provide extremely valuable reagents for basic research. HSV has many attractive features as a gene therapy vector; the genome is very large and can accommodate large inserts, it efficiently infects most cell types both dividing and non-dividing from a broad range of species, it naturally undergoes a latent infection in neurons that causes no detectable damage to the infected cell or can undergo a lytic infection that is cytotoxic, and antiviral drugs are available to treat adverse events.

In the realm of cancer therapy, we are developing a number of different vector strategies for the treatment of tumors: (i) oncolytic, replication-competent HSV vectors that replicate selectively in neoplastic cells and spread within the tumor in vivo, yet are nonpathogenic to normal tissue; (ii) transcriptionally-targeted HSV vectors, where viral replication and associated cytotoxicity are driven by cell-specific promoters/enhancers; and (iii) defective vector / replication-competent helper HSV combinations for the high-level expression of immune-modulatory and 'suicide' genes. Oncolytic vectors are generated by mutating the virus so that it is attenuated for growth in non-dividing cells, but continues to replicate in tumor cells. The virus constructs are tested in various in vivo tumor models for efficacy and mechanism of action, and their safety assessed. Our studies initially concentrated on brain tumors, however this technology is applicable to most tumors. For example, we are examining prostate and breast cancer therapy. The tumor models include; human xenografts in nude mice or syngeneic mouse tumor implants (subcutaneous, intracranial, orthotopic) and spontaneous tumors in transgenic mice. The combination of HSV vectors with conventional cancer treatment modalities, such as chemotherapy and radiation therapy, to enhance efficacy is also being evaluated.

A recent important discovery was that attenuated, replication-competent HSV vectors induce a specific anti-tumor immune response, in essence acting as an in situ cancer vaccine. To enhance the anti-tumor immune response we are using defective vector / replication-competent helper HSV combinations, where the defective HSV vectors provide high-level expression of immune-modulatory genes, such as IL-12, GM-CSF, and soluble dimeric B7-1, in tumors in situ. We are also constructing recombinant, oncolytic vectors containing these transgenes. The role of immune responses in the brain and their effect on brain tumors is an important question being pursued.

As an alternate strategy for viral tumor therapy, we developed transcriptionally-targeted HSV, where viral replication and associated cytotoxicity are restricted to a specific cell type by the regulated expression of an essential immediate-early viral gene product. As a proof-of-principle, an albumin promoter/enhancer regulated HSV was constructed which specifically replicated in and killed hepatocellular carcinoma cells in vitro and in vivo. A number of tumor cell-specific regulatory sequences (ie., nestin, midkine, erbB2) are being tested for breast and brain tumors.

A second focus of the laboratory is the use of defective HSV vectors for gene delivery to the nervous system in order to study gene function and alter cellular physiology. Defective HSV vectors are a highly efficient means of transducing neural cells in vitro and in vivo. Two gene products in particular are being studied: (I) Glutamic acid decarboxylase (GAD), for the novel synthesis of GABA, in order to inhibit excitatory pathways as a therapeutic approach to epilepsy and pain; and (2) Neural cell adhesion molecule L1, involved in neurite outgrowth and neuronal migration, which may facilitate neural regeneration. Clinical mutations in L1 lead to a variety of developmental disorders of the nervous system, including mental retardation and hydrocephalus, and we are examining the effects of these mutations on L1 function.

Current Research Areas:

Development of new oncolytic HSV vectors
Use of oncolytic HSV vectors in transgenic mouse tumor models
Immunotherapy in for brain tumors
Generation of helper-free defective HSV vectors
Novel GAD expression in the brain to modulate excitatory networks
Structure/function studies of clinical mutations in L1

Links

• MGH Neuroscience Center
• MGH Neuroscience Center PCR Core
• HMS Microbiology and Molecular Genetics Department
• Dana-Farber/Harvard Cancer Center
• HMS Center for Neurofibromatosis and Allied Disorders
• Harvard Center for Neurodegeneration and Repair
  

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