Vector development:
Gene therapy for liver disease
Members
Hilla Giladi, Ph.D., Head Scientist;
Mali Ketzinel-Gilad, Ph.D.
Reba Condiotti, MS.c.;
Sharon Dagan, M.Sc., Ph.D. Student;
Hana Wald, Ph.D.;
Mila Rivkin, B.Sc.
Scientific activities
- Induction of apoptosis in Hepatitis C infected cells
- Development of edible vaccine against Hepatitis A virus in transgenic tomato plants
- Development of FIV-based lentiviral vectors for transduction of hepatocytes for treatment of liver disease
- RNA interference of HBV gene expression
- Development of an antiviral therapeutic agent through the generation of HBV-dependent group I intron ribozymes using in vitro evolution techniques
- Development of animal models of hepatitis B and C viral infection
- The vector development service
Research interests
- Development of viral vectors for gene therapy: recombinant adenoviral vectors, adeno-associated virus (AAV), lentiviral vectors;
- Production of viral particles in basic edible vegetable crops (e.g. tomato): development of vaccines and gene targeting vehicles with tissue tropism;
- Gene therapy for treatment of Hepatitis B and C viral infections;
- Development of non-primate lentiviral vectors for treatment of liver disease: feline immunodeficiency-based constructs.
Collaborations
Liver Unit, Hadassah University Hospital, Jerusalem, Israel;
Prof. Ernest Winocour, Dept. of Molecular Genetics, Weizmann Institute ;
Prof. Garry Nolan, Dept. of Microbiology and Immunology, Stanford University Medical Center, California;
XTL, Ltd., Ness Ziona, Israel
Intelligene, Ltd., Jerusalem, Israel
Therapeutics to Control and Manipulate
Chemokine Dependent Cell Migration
Members
Amnon Peled, Ph.D.,Head scientist;
Hana Wald, Ph.D., Research Scientist;
Suzana Franitza, Ph.D., Postdoctoral Fellow
Michal Dagan-Berger, M.Sc., Ph.D. Student
Ori Wald, B.Sc., M.D/Ph.D. Student
Merav Darash-Yahana, M.Sc., Ph.D. Student
Katia Beider, B.Sc., M.Sc. Student;
Boaz Pal, B.Sc., M.Sc. Student
Shani Avniel, B.Sc., M.Sc. Student
Scientific Activities
Developing novel therapeutics to control and manipulate chemokine dependent cell migration
Collaborations
Ronen Alon, Ph.D., Dept. of Immunology, The Weizmann Institute of Science, Rehovot, Israel. Nature of collaboration: NK adhesion and rolling
Stefan Brocke, M.D., Ph.D., Dept. of Pathology, Hadassah University Hospital, Jerusalem, Israel. Nature of collaboration: Chemokine, SDF-1, in inflammation;
Tsvee Lapidot, Ph.D., Weizmann Institute of Science, Rehovot, Israel Nature of collaboration: Stem cell research;
Arnon Nagler, M.D., Sheba Hospital, Tel Hashomer, Israel. Nature of collaboration: Stem cell/NK cells;
Placental Protein 14: Mechanism of action and therapeutic potential

Members
Jacob Rachmilewitz, Ph.D., Head Scientist
Zipora Borovsky,
Galit Mishan-Eisenberg,
Einat Yaniv,
Scientific activities
Placental Protein 14: A unique immunomodulator
Research Interests
Placental Protein 14's mechanism of action and evaluation of it's therapeutic potential;
General aspects of T cell activation.
International Scientific Collaborations
Dr. Mark L. Tykocinsky, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia
MRI as a tool for the study of
vascular remodeling
Members
Rinat Abramovitch, Ph.D., Head Scientist;
Hila Harel, B.Sc., M.Sc. Student;

From left to right: Rinat & Hila
Scientific activities
MRI as a tool for the study of vascular remodeling
Collaborations*
Applying a new non-invasive technique for quantitative assessment of tumor angiogenesis to the clinic - in collaboration with Prof. Tali Sigal, Dept. of Neurooncology, Hadassah, and Prof. Moshe Gomori, Dept. of Neurordiology, Hadassah.
Development of MRI methods for evaluating the feasibility of VEGF-mediated pro-angiogenic therapy - in collaboration with Prof. Eli Keshet, Dept. of Molecular Biology, Hebrew University.
Assessment of anti-angiogenic therapy using MRI - in collaboration with Prof. Tali Sigal, Dept. of Neurooncology, Hadassah.
Analysis of the angiogenic potential of heparanase - in collaboration with Prof. Israel Vlodavsky, Dept. of Oncology, Hadassah.
Angiogenic process in partial hepatectomy - in collaboration with Prof. Eithan Galun and Dr. Eithan Gross a pediatric surgeon.
* for more on these collaborations see MRI as a tool for the study of vascular remodeling.
Molecular mechanisms of
hepatitis C virus induced liver carcinogenesis
Members
Daniel Goldenberg, Ph.D., Head Scientist;
Esther Korzin-Bez, M.Sc.;
Lina Mizrahi, M.Sc.;
Naama Hecht, M.Sc., Ph.D. student;
Mark Katzenellenbogen, M.Sc., Ph.D. student.

From left to right: Esther, Daniel, Naama, Mark, Lina
Scientific activities
Production of transgenic mice expressing separate HCV proteins
Gene profiling of mouse models for hepatocellular carcinoma
Pharmacogenomics: genetic diagnostics for custom-made gene therapy
Collaborations
Our group collaborates with researchers from:
The Goldyne Savad Institute of Gene Therapy:
- on the immune response to HCV infection - in collaboration with Dr. Amnon Peled, Dr. Jacob Rachmilewitz and their research groups;
- on live mice imaging using a luciferase expression system and CCD photon detection camera - in collaboration with Evelyne Zeira;
Hadassah Hospital:
- on the histology of hepatocellular carcinoma in collaboration with Dr. Orit Pappo;
-on MRI scanning of mouse liver in live mice in collaboration with Dr. Rinat Abramovitz;
Weizmann Institute:
- on cluster analysis of the results of gene profiling experiments- in collaboration with Prof. Eytan Domany;
XTL, ltd.:
- on hepatitis C virus biology - in collaboration with researchers of "XTL", ltd. (Nes Ziona, Israel).
Hyper-IL-6 protein and gene therapy in
the treatment of liver failure and neoplasia
Members
Jonathan Axelrod, Ph.D., Head Scientist
Eithan Galun M.D., Head of Gene Therapy Institute
Yael Nechemia, M.Sc. Student
Carmit Orfaig, M.Sc. Student
Former Members
Naama Hecht, M.Sc.;
Jonathan Raub
Uli Denz

From left to right: Yael, Jonathan and Carmit
Scientific activities
Hyper-IL-6 protein and gene therapy in the treatment of liver failure and neoplasia (overview)
Reversal of fulminant hepatic failure by Hyper-IL-6 gene therapy *©(zipped power-point presentation. click to download)
An IL-6/sIL-6R fusion protein, expressed by hyrdrodynamics-based transfection, cooperates synergistically with hepatocyte growth factor to induce hepatocyte replication in vivo
Mechanisms of Hyper-IL-6 enhanced liver regeneration and its application in the treatment of organ failure and in gene therapy strategies.
Exploration of the anti-neoplastic utility of a novel oncolytic adenoviral vector encoding an IL-6/sIL-6R fusion protein
* "Hyper IL-6 gene therapy reverses fulminant hepatic failure", by N. Hecht et al., from Molecular Therapy Volume 3, 683-687, © copyright 2001, Elsevier Science (USA), reproduced by permission of the publisher. Single copies of the article can be downloaded and printed for the reader's personal research and study.
International Scientific Collaborations
Prof. Dr. Stefan Rose-John Director, Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Medical Faculty, Kiel, Germany
For many years, the Goldyne Savad Gene Therapy Institute, under the directorship of Prof. Eithan Galun, has enjoyed an active and fruitful collaboration with Prof. Rose-John and his laboratory. This collaboration centers upon the genetically engineered, Interleukin-6 (IL-6) based designer cytokine, appropriately named Hyper-IL-6 because of its super agonistic qualities, that was originally developed in the laboratory of Prof. Rose-John. The therapeutic potential of Hyper-IL-6 in the treatment of fulminant hepatic failure (FHF) as shown in experiments performed by Prof. Galun, E. Zeira, et al. (2000), was the first major product of this collaboration. Since then, the study of the use of Hyper-IL-6 in gene therapy strategies for the treatment of liver disease and neoplasia, and the molecular mechanism in these processes have been the major thrusts of our collaboration.
Human embryonic stem cells:
A new avenue for treatment of human diseases
Members
Benjamin Reubinoff, M.D., Head scientist;
Vitaly Ablamunits, M.D., Ph.D.
Israel Ben-Dor, Ph.D.;
Hanita Khaner, Ph.D.;
Etti Ben Shushan, Ph.D.;
Michal Gropp, Ph.D.
Tikva Tako Turetsky, M.Sc.
Pavel Itsykson, M.Sc., Ph.D. Student
Orna Singer, M.Sc.
Maria Idelson, M.Sc., Ph.D. Student
Shelly Tannenbaum, B.Sc.

From left to right: Back row: Benny (Benjamin), Vitaly, Pasha (Pavel), Israel. Front row: Orna, Shelly, Masha (Maria), Michal, Hanita, Tikva, Etti.
Scientific activities
Human embryonic stem cells: A new avenue for treatment of human diseases (overview)
Neural progenitors from human ES cells (a specific project)
Collaborations
Our group collaborates with researchers from:
The Goldyne Savad Institute of Gene Therapy:
Prof. Eithan Galun - on Genetic modification of human embryonic stem cells
The objective of the project is to develop methodologies for the genetic modification of human ES cells. Genetic modification of human ES cells is of significant importance for various applications. It may facilitate genetic selection of pure stem cell population or specific types of differentiated cells. Genetically modified human ES cells could be used to deliver and express foreign DNA in the course of gene therapy. Genetic alterations of human ES cells such as knockout of MHC locus may be used to generate clones that will not induce immune response after transplantation. Modification of gene expression by human ES cells may be useful for the study of function of new genes, as well as for the creation of human disease models in vitro.
Dr Amnon Peled - on Hematopoietic differentiation of human embryonic stem cells.
The differentiation of human ES cells along the hematopoietic lineage is characterized in this project and methods for the establishment of pure populations of hematopoietic stem cells are developed. This technology may allow the use of human ES cells as an unlimited source of blood cells for bone marrow transplantation and transfusion therapies.
Hadassah Hospital
Prof. Tamir Ben-Hur, Department of Neurology - on Neural differentiation of human embryonic stem cells.
Human embryonic stem cells may serve as a renewable donor source of neural cells for transplantation in a variety of neurodegenerative disorders.
The objective of the project is to develop the technology that will facilitate the utilization of human ES cells for cell therapy of the nervous system.
Dr. Gil Leibowitz, Department of Endocrinology and Metabolism - on Differentiation of human ES cells into pancreatic cells.
Islet transplantation can result in insulin independence and potentially cure of Type 1 diabetes. A major obstacle for widespread use of islet transplantation is limited tissue supply. The goal of the project is to generate an unlimited source of pancreatic b-cells derived from human ES cells that can be used for transplantation to patients with diabetes.
Others Quark Biotechnology Incorporation (QBI)
The discovery of novel genes that regulate the growth and differentiation of human ES cells.
The derivation of pluripotent stem cells from human embryos is a major scientific breakthrough. Nevertheless to realize the great potential of human ES cells we need to further uncover the key genes and factors that govern the growth and differentiation of these cells. The focus of the project is to identify genes critical to stem cell renewal and differentiation.
Imaging transgene expression in live animals
using a bioluminescence camera CCCD
Members
Eithan Galun, M.D., Head scientist, Head of the Institute;
Evelyne Zeira, Research Scientist
Hagit Yotvat, Technician - CCCD camera;


From left to right: Hagit, Evelyne, and the CCCD camera
We have applied a new light detection cooled CCD camera (CCCD) for in-vivo assessment of gene expression from commonly used gene therapy delivery systems such as ex-vivo manipulated cells, viral vectors and naked DNA, without the need of animal sacrifice.
This method enables the continuously detection of gene expression without killing the animals. The technology takes advantage of the light emitted for luciferase expressing cells following the administration of the luciferin substrate. The light is detected by an ultra sensitive CCCD system. This technology enables to determine in a semi quantitative manner the efficiency of infection/transfection of various viral and non-viral delivery systems as well as regulatory effects e.g. promoter specificity. This method was proved to be efficient in monitoring real time gene expression in a wide spectrum of tissues. These tissues include bone, muscle, salivary glands, dermis, liver, peritoneum, testis, teeth, prostate and bladder in living mice and rats.
Scientific activities
Imaging transgene expression in live animals (PubMed abstract)
Molecular imaging of the skeleton: Quantitative real time bioluminescence Monitoring gene expression in skeletal repair and development
Effect of anti Her2 Immunotoxins on prostate adenocarcinoma in vitro and in vivo
In vivo continuous detection of metastasis development using a luciferase-based imaging technology of human acute myeloblastic leukemia (AML) and chronic myelocytic leukemia (CML) in NOD/SCID mice
Spectral Confinement of Laser Tissue Interaction - A novel therapeutic platform for metabolic, degenerative, autoimmune, infectious and malignant diseases
Future research interests for the development of this technology:
Organ distribution of luciferin
Assessment of tumor models by implantation of Luc expressing cells
Determination of viral vectors delivery systems
Determination of non-viral vectors delivery systems
Collaborations
Our group collaborates with researchers from:
The Goldyne Savad Institute of Gene Therapy:
Dr. Amnon Peled
The Hebrew University - Hadassah Medical School
Prof. Alik Honigman, Dept. of Virology. Investigating the role of CREB and CREB mutant in tumor development.
Prof. Dan Gazit, Dept. of Oral Biology, Dental School
Prof. Eitan Yefenof, Dept. of Immunology
Prof. David Naor, Dept. of Immunology
Dr. Ofer Mandelboim, Dept. of Immunology
Dr. Eyal Mishani and Prof. Roland Chishin, Dept. of Nuclear Medicine. Development of novel gene expression PET detection systems.
Non-Viral gene delivery,
Anti-viral vaccination and
Other research projects at the Institute
Members
Eithan Galun, M.D., Head scientist, Head of the Institute;
Evelyne Zeira, Research Scientist;
Uri Arad, M.D./Ph.D. Student;
Tikva Dadon, M.Sc. Student;
Scientific Activities
Allogeneic & xenogeneic pancreatic islet cell transplants into the bone marrow space
Laser induced gene delivery
Research Interests
Novel methods for non-viral gene delivery
Development of methods for anti-viral vaccination
The bone marrow as an immunoprivileged site
SV40 for liver directed gene delivery
Assessing the oncolytic properties of the New Castle Virus (NDV) vaccine
Development of tumor specific gene expression cassettes
Collaborations with Hadassah Hospital and Medical School Groups
Prof. Dinah Ben-Yehuda (Dept. of Hematology): Development of a novel method for erythropoietin expression vector gene delivery to the muscle using a laser beam.
Prof. Iri Liebergall (Dept. of Orthopedics): Development of human mesenchymal cell based therapy for complex orthopedic conditions. Through this project Shaul Bait M.D. will conduct his Ph.D. thesis.
Dr. Gideon Zamir (Dept. of Surgery): Assessing the mechanisms responsible for the short live adenovirus transgene liver expression.
Dr. Yoram Weiss (Dept. of Anesthesiology): Assessment of the potential therapeutic role of HSP 70 in ARDS lung.
Prof. Arnold Freeman, Prof. Yevgeni Libson, Prof. Tali Siegal, Prof. Zichria Rones and Prof. Amos Panet (Pediatric Oncology Unit, and the Departments of Radiology, Neurology and Virology): Development of the New Castle Virus vaccine as an oncolytic agent for brain tumors.
Prof. Tali Siegal, Prof. Haim Ovadiah and Prof. Moshe Gomori (Departments of Neurology and Radiology): Development of novel methods for brain gene delivery.