Higgins Professor of Neurosurgery
Harvard Medical School
Chief, Neurosurgical Service
Massachusetts General Hospital
Members of the Martuza Lab:

Samuel David Rabkin, PhD
Associate Professor of Surgery
(Microbiology and Molecular Genetics)
Harvard Medical School
Associate Virologist in Neurosurgery
Massachusetts General Hospital

Giulia Fulci PhD - Instructor in Surgery (Neurosurgery), Harvard Medical School - [University of Lausanne, Switzerland]

Ta-Chiang Liu MD - Research Fellow in Surgery (Neurosurgery), Harvard Medical School - [National Yang Ming University, Taiwan, PhD Imperial College, London, UK]

Brent Passer PhD, - Instructor in Surgery (Neurosurgery), Harvard Medical School - [University of Alabama-Birmingham, Post-doc NIAID (L. D'Adamio)]

Cécile Zaupa PhD, Research Fellow in Surgery (Neurosurgery) Harvard Medical School - [University of Lyon, France]

Tooba A.Cheema, PhD, Research Fellow in Surgery [Neurosurgery], Harvard Medical School - [University of Michigan]

Hiroaki Wakimoto, MD, PhD - Instructor in Surgery (Neurosurgery), Harvard Medical School - [ ]

Students:
Molecular Neurosurgery Laboratory - Gene Therapy
Oncolytic HSV G47 plaques (blue X-gal stain) on Vero cells.

Lab Contact Information:

Richard B. Simches Research Center,
Brain Tumor Research Center,
Massachusetts General Hospital
CPZN-3-3800
617-726-6817 (Phone)
617-643-3422 (Fax)

Research Interests:

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, while 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.

Current Research Areas:

  • Development of new oncolytic HSV vectors
  • Use of oncolytic HSV vectors in transgenic mouse tumor models
  • Combinational therapies with oncolytic HSV vectors
  • Immunotherapy for brain tumors
  • Translation of oncolytic HSV vectors to the clinic
  • Novel GAD expression in the brain to modulate excitatory networks
  • Structure/function studies of clinical mutations in L1

Oncolytic HSV Vectors and Cancer Therapy

Wild-type HSV immunoreactive cells in the cortex in animal with HSV encephalitis [William Hunter].
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. A recent important discovery was that oncolytic HSV vectors induce a specific anti-tumor immune response, in essence acting as an in situ cancer vaccine. This has directed us towards immunotherapeutic strategies. The combination of HSV vectors with conventional cancer treatment modalities, such as chemotherapy and radiation therapy, to enhance efficacy is also being evaluated.

G47replication (blue X-gal stain) in a breast tumor implant in the brain 5 days after virus injection
[Renbin Liu].

Current Projects:

Development of new oncolytic HSV vectors.
We are continuing to construct new oncolytic HSV vectors with enhanced efficacy [PMID: 11353831]. A major advance has been the generation of HSV-BAC (bacterial artificial chromosome) plasmids that can be manipulated in bacteria and biochemically. These constructs are useful for rapidly inserting a variety of therapeutic transgenes into defined sites in the HSV genome.
Transcriptionally-targeted oncolytic HSV.
In this strategy, viral replication and associated cytotoxicity are restricted to a specific cell type by the regulated expression of an essential immediate-early viral gene product (ICP4). 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 [PMID: 9188579]. A number of tumor cell-specific regulatory sequences are being tested for brain, prostate, and colorectal tumors.

Virotherapy for Prostate Cancer.

G92A plaque
(brown, anti-ICP4 immunohistochemistry) on Hep3B hepatoma cells [Anu Iyer].

Transgenic Mouse Models for Therapeutic Evaluation.

We are using transgenic mouse models that spontaneously develop tumors as representative models to evaluate oncolytic HSV therapy [[PMID: 15735042].
Virotherapy for Neurofibromatosis.

Oncolytic HSV immunotherapy.
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 [PMID: 11196154]. We are also constructing and evaluating recombinant, oncolytic vectors containing these transgenes [PMID: 16179929].


Interaction of oncolytic HSV with dendritic cells.

Oncolytic HSV and antiangiogenesis.

Combination Therapies.

Defective HSV Vectors for Gene Delivery to the Nervous System

Defective HSV vectors are a highly efficient means of transducing
neural cells in vitro and in vivo.
Human schwann cells expressing GFP
after infection with defective HSV vector
[Usha MacGarvey]

Novel GAD expression in the brain to modulate excitatory networks. Glutamic acid decarboxylase (GAD), for the novel synthesis of GABA, in order to inhibit excitatory pathways as a therapeutic approach to epilepsy and pain [PMID: 12867983]

Structure/function studies of clinical mutations in L1. Neural cell adhesion molecule L1 is 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 [PMID: 10908608].


Lab Alumni: [Name / Current Position]

  • Manish Aghi MD/PhD - Resident / Clinical Fellow in Surgery (Neurosurgery)
  • Toshihiko Kuroda MD/PhD
  • Will Curry, Instructor in Neurosurgery, MGH
  • Faris Farassati, Postdoc Mayo Clinic, Rochester MN
  • Hiroshi Fukuhara, Instructor in Urology, University of Tokyo Hospital, Japan
  • Yasushi Ino, Instructor in Neurosurgery, University of Tokyo Hospital, Japan
  • Andreas Kurtz, Robert Koch Institute, Berlin, Germany
  • Renbin Liu Associate Professor in Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
  • Tomoki Todo, Assistant Professor of Neurosurgery, University of Tokyo Hospital, Japan
  • Susan Varghese, Booz Allen Hamilton Inc.
  • Tingguo Zhang, Associate Professor of Pathology, Shandong University Hospital, Jinan, PR China
Disclaimer About Medical Information: The information and reference materials contained herein is intended solely for the information of the reader. It should not be used for treatment purposes, but rather for discussion with the patient's own physician.
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