Updated December 2009
Director
Goldyne Savad Institute of Gene Therapy
Sam and Ellie Fishman Chair in
Gene Therapy
Phone: 972-2-677-8589
Fax: 972-2-6430982
Email: EithanG@hadassah.org.il
Academic Rank
Professor of Medicine, Hebrew University, Jerusalem, Israel
Affiliation
Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Education
1972-78: M.D. Sackler Medical School, Tel Aviv Univ., Israel
1979-83: Medical Officer
1983-88: Residency, Internal Medicine, Hadassah Univ. Hospital
1988-89: Chief Resident, Internal Medicine, Hadassah Univ. Hospital
Research fellowships
1981-1983: Heller Institute of Physiology, Tel Hashomer Hospital
1986-1987: Research Fellow, Weizmann Institute of Science, Rehovot
1989-1991: Molecular Hepatology Laboratory and MGH Cancer Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129
Awards
1987: Outstanding Lecturer in Internal Medicine, the Hebrew University, School of Medicine, Jerusalem
1989: Rothchild Fellowship Award
1990: Henry Leon Weiler Fellowship Award
1992: Naftali Foundation Award
2000: Chair, Sam and Ellie Fishman Cathedra in Gene Therapy
Patents
Blum HE, Galun E, Liang T-J, Wands JR. Methods for preventing viral replication, field: march 1992, serial #: 07/846,328 ,U.S.A. Approved 1994 .
Galun E, Nahor O, Blum HE. Prevention of HBV infection by hIL-6 antagonists. Field: March 1997, serial #: 08/795,473, U.S.A. Approved July 1999. US Patent # 6,217,858.
Galun E, Peters M, Jonathan Axelrod, Rose-John S. IL-6/sIL-6 complex for treatment of liver failure, field: June 1998, serial #5,919,763 USA. Approved July 1999.
Galun E and Galun E. Development of oral vaccination to human viral pathogens through the production of viral particles in transgenic plants. IL01/00550. Submitted 2001.
Galun E, Zeira E, Ketzinel M, Mitchell L, Giladi H. Vaccination for hepatitis A virus. 09/596,060. Submitted 2001.
Axelrod JA, Galun E, Rose-John S, Denz U. An sIL-6R/IL-6 Fusion Protein Cooperates Synergistically with HGF to Stimulate Hepatocyte Proliferation In Vivo. 60/352,207. Submitted 2001.
Axelrod JA, Galun E, Rose-John S. Oncolytic viruses. Submitted 2001.
Zeira E, Manevitch A, Khatchatouriants A, Hemo I, Lewis A, Galun E. Controlled Laser Treatment for Non-Invasive Tissue. Priority date April 2002. March 2003 filing of PCT/IL03/00260.
Research interests
Liver directed gene therapy; development of delivery methods; animal models; novel vaccination approaches and specific therapeutics in cancer.
Selected recent publications
Israel A, Sharan R, Ruppin E, Galun E. 2009. Increased microRNA activity in human cancers. PLoS ONE 4(6):e6045.
Zorde-Khvalevsky E, Abramovitch R, Barash H, Spivak-Pohis I, Rivkin L, Rachmilewitz J, Galun E, Giladi H. 2009.Toll-like receptor 3 signaling attenuates liver regeneration. Hepatology 50(1):198-206.
Matouk IJ, Abbasi I, Hochberg A, Galun E, Dweik H, Akkawi MHighly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. 2009. Eur J Gastroenterol Hepatol 21:688-692.
Ram SE, Galun E. 2009. AAV2-GDNF Gene Therapy for Parkinson's Disease. Hum Gene Ther 20(5):430-1.
Rudich N, Zamir G, Pappo O, Shlomai Z, Faroja M, Weiss ID, Wald H, Galun E, Peled A, Wald O. 2009. Focal liver necrosis appears early after partial hepatectomy and is dependent on T cells and antigen delivery from the gut. Liver Int. 2009 Jun 16.
Klopstock N, Katzenellenbogen M, Pappo O, Sklair-Levy M, Olam D, Mizrahi L, Potikha T, Galun E, Goldenberg D. 2009. HCV tumor promoting effect is dependent on host genetic background. PLoS ONE. 4(4):e5025.
Beider K, Abraham M, Begin M, Wald H, Weiss ID, Wald O, Pikarsky E, Abramovitch R, Zeira E, Galun E, Nagler A, Peled A. 2009. Interaction between CXCR4 and CCL20 pathways regulates tumor growth. PLoS ONE 4(4):e5125.
Abraham M, Beider K, Wald H, Weiss ID, Zipori D, Galun E, Nagler A, Eizenberg O, Peled A. 2009. The CXCR4 antagonist 4F-benzoyl-TN14003 stimulates the recovery of the bone marrow after transplantation. Leukemia
Aviezer D, Brill-Almon E, Shaaltiel Y, Hashmueli S, Bartfeld D, Mizrachi S, Liberman Y, Freeman A, Zimran A, Galun E. 2009. A plant-derived recombinant human glucocerebrosidase enzyme--a preclinical and phase I investigation. PLoS ONE 4(3):e4792.
Tzur G, Levy A, Meiri E, Barad O, Spector Y, Bentwich Z, Mizrahi L, Katzenellenbogen M, Ben-Shushan E, Reubinoff BE, Galun E. 2008. MicroRNA expression patterns and function in endodermal differentiation of human embryonic stem cells. PLoS ONE 3(11):e3726.
Barash H, Gross E, Edrei Y, Pappo O, Spira G, Vlodavsky I, Galun E, Matot I, Abramovitch R. 2008. Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia. Hepatology 48(4):1232-41.
Ben Moshe T, Kang TB, Kovalenko A, Barash H, Abramovitch R, Galun E, Wallach D. 2008. Cell-autonomous and non-cell-autonomous functions of caspase-8. Cytokine Growth Factor Rev. 19(3-4):209-17.
Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E, Axelrod JH. 2008. IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury. J Am Soc Nephrol 19(6):1106-15.
Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Jacob-Hirsch J, Amariglio N, Rechavi G, Domany E, Galun E, Goldenberg D. 2007. Molecular mechanisms of liver carcinogenesis in the mdr2-knockout mice. Mol Cancer Res. 5(11):1159-70.
Klopstock N, Levy C, Olam D, Galun E, Goldenberg D. 2007. Testing transgenic regulatory elements through live mouse imaging. FEBS Lett. 581(21):3986-90.
Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E. 2007. The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2(9):e845.
Zeira E, Manevitch A, Manevitch Z, Kedar E, Gropp M, Daudi N, Barsuk R, Harati M, Yotvat H, Troilo PJ, Griffiths Ii TG, Pacchione SJ, Roden DF, Niu Z, Nussbaum O, Zamir G, Papo O, Hemo I, Lewis A, Galun E. 2007. Femtosecond laser: a new intradermal DNA delivery method for efficient, long-term gene expression and genetic immunization. FASEB J. 21(13):3522-33.
Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, Nagler A, Peled A. 2007. Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-benzoyl-TN14003. Stem Cells 25(9):2158-2166.
Wald O, Weiss ID, Galun E, Peled A. 2007. Chemokines in hepatitis C virus infection: Pathogenesis, prognosis and therapeutics. Cytokine 39(1):50-62.
Barash H, Gross E, Matot I, Edrei Y, Tsarfaty G, Spira G, Vlodavsky I, Galun E, Abramovitch R. 2007. Functional MR Imaging during Hypercapnia and Hyperoxia: Noninvasive Tool for Monitoring Changes in Liver Perfusion and Hemodynamics in a Rat Model. Radiology 243(3):727-35.
Ben Moshe T, Barash H, Kang TB, Kim JC, Kovalenko A, Gross E, Schuchmann M, Abramovitch R, Galun E, Wallach D. 2007. Role of caspase-8 in hepatocyte response to infection and injury in mice. Hepatology 45(4):1014-1024.
Rivo J, Zeira E, Galun E, Einav S, Linden J, Matot I. 2007. Attenuation of reperfusion lung injury and apoptosis by A2A adenosine receptor activation is associated with modulation of Bcl-2 and Bax expression and activation of extracellular signal-regulated kinases. Shock 27(3):266-273.
Zamir G, Zeira E, Gelman AE, Shaked A, Olthoff KM, Eid A, Galun E. 2007. Replication-deficient Adenovirus Induces Host Topoisomerase I Activity: Implications for Adenovirus-mediated Gene Expression. Mol Ther. 15(4):772-81.
Galun E, Terrault NA, Eren R, Zauberman A, Nussbaum O, Terkieltaub D, Zohar M, Buchnik R, Ackerman Z, Safadi R, Ashur Y, Misrachi S, Liberman Y, Rivkin L, Dagan S. 2007. Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: Safety and antiviral activity. J Hepatol 46(1):37-44.
Khvalevsky E, Rivkin L, Rachmilewitz J, Galun E, Giladi H. 2007. TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. J Cell Biochem 100(5):1301-12.
Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Barash H, Domany E, Galun E, Goldenberg D. 2007. Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice. Mol Cancer Ther. 6(4):1283-91.
Katzenellenbogen M, Pappo O, Barash H, Klopstock N, Mizrahi L, Olam D, Jacob-Hirsch J, Amariglio N, Rechavi G, Mitchell LA, Kohen R, Domany E, Galun E, Goldenberg D. 2006. Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice. Cancer Res 66(8):4001-10.
Ketzinel-Gilad M, Shaul Y, Galun E. 2006. RNA interference for antiviral therapy. J Gene Med 8(8):933-50. Review.
Schiano TD, Charlton M, Younossi Z, Galun E, Pruett T, Tur-Kaspa R, Eren R, Dagan S, Graham N, Williams PV, Andrews J. 2006. Monoclonal antibody HCV-AbXTL68 in patients undergoing liver transplantation for HCV: results of a phase 2 randomized study. Liver Transpl 12(9):1381-9.
Mitchell LA, Joseph A, Kedar E, Barenholz Y, Galun E. 2006. Mucosal immunization against hepatitis A: antibody responses are enhanced by co-administration of synthetic oligodeoxynucleotides and a novel cationic lipid. Vaccine 19:24(25):5300-10.
Ben-Dor I, Itsykson P, Goldenberg D, Galun E, Reubinoff BE. 2006. Lentiviral vectors harboring a dual-gene system allow high and homogeneous transgene expression in selected polyclonal human embryonic stem cells. Mol Ther 14(2):255-67.
Matot I, Weiniger CF, Zeira E, Galun E, Joshi BV, Jacobson KA. 2006. A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion. Crit Care 10(2):R65.
Wald O, Izhar U, Amir G, Avniel S, Bar-Shavit Y, Wald H, Weiss ID, Galun E, Peled A. 2006. CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma. J Immunol 177(10):6983-90.
Wald O, Weiss ID, Wald H, Shoham H, Bar-Shavit Y, Beider K, Galun E, Weiss L, Flaishon L, Shachar I, Nagler A, Lu B, Gerard C, Gao JL, Mishani E, Farber J, Peled A. 2006. IFN-{gamma} Acts on T Cells to Induce NK Cell Mobilization and Accumulation in Target Organs. J Immunol 176(8):4716-29.
Ketzinel-Gilad M, Zauberman A, Nussbaum O, Shoshany Y, Ben-Moshe O, Pappo O, Felig Y, Ilan E, Wald H, Dagan S, Galun E. 2006. The use of the hydrodynamic HBV animal model to study HBV biology and anti-viral therapy. Hepatology Res.
Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Rasooly L, Greenbaum E, Rozenman-Yair S, Panet A, Libson E, Irving CS, Galun E, Siegal T. 2006. Phase I/II Trial of Intravenous NDV-HUJ Oncolytic Virus in Recurrent Glioblastoma Multiforme. Mol Ther 13:221-228.
Avniel S, Arik Z, Maly A, Sagie A, Basst HB, Yahana MD, Weis ID, Pal B, Wald O, Ad-El D, Fujii N, Arenzana-Seisdedos F, Jung S, Galun E, Gur E, Peled A. 2006. Involvement of the CXCL12/CXCR4 pathway in the recovery of skin following burns. J Invest Dermatol 126(2):468-76.
Eren R, Landstein D, Terkieltaub D, Nussbaum O, Zauberman A, Ben-Porath J, Gopher J, Buchnick R, Kovjazin R, Rosenthal-Galili Z, Aviel S, Ilan E, Shoshany Y, Neville L, Waisman T, Ben-Moshe O, Kischitsky A, Foung SK, Keck ZY, Pappo O, Eid A, Jurim O, Zamir G, Galun E, Dagan S. 2006. Preclinical evaluation of two neutralizing human monoclonal antibodies against hepatitis C virus (HCV): a potential treatment to prevent HCV reinfection in liver transplant patients. J Virol 80(6):2654-64.
Dagan-Berger M, Feniger-Barish R, Avniel S, Wald H, Galun E, Grabovsky V, Alon R, Nagler A, Ben-Baruch A, Peled A. 2006. Role of CXCR3 carboxyl-terminus and third intracellular loop in receptor-mediated migration, adhesion and internalization in response to CXCL11. Blood. 107(10):3821-31.
Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Asian H, Galun E, Rachmilewitz J. 2005. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T cell unresponsiveness. Blood 105:2214-9.
Grez M, Galun E, Moullier P. 2005. The Twelfth Annual Meeting of the European Society of Gene Therapy. Molecular Therapy 11:178-9.
Arad U, Zeira E, Abd El-Latif M, Pappo O, Mitchell L, Galun E, Oppenheim A. 2005. Liver-targeted gene therapy by SV40 based vectors using the hydrodynamic injection method. Hum Gene Ther 16:361-71.
Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, Mei-Zahav C, Mizrachi S, Liberman Y, Iaina A, Kaplan E, Podjarny E, Zeira E, Harati M, Casadevall N, Shani N, Galun E. 2005. Human erythropoietin gene therapy for patients with chronic renal failure. Blood 106(7):2280-6 .
Shai E, Palmon A, Panet A, Marmary Y, Curran MA, Nolan GP, E Galun, Condiotti R. 2005. Prolonged transgene expression in murine salivary glands following non-primate lentiviral vector transduction. Mol Ther 12(1):137-43.
Arad U, Axelrod J, Ben-nun-Shaul O, Oppenheim A, Galun E. 2004. Hepatis B virus enhances transduction of human hepatocytes by SV40-based vectors. J Hepatol 40:520-6.
Abramovich R, Tavor E, Jacob-Hirsch J, Zeira E, Amariglio N, Pappo O, Rechavi G, Galun E, Honigman A. 2004. A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. Cancer Res 64:1338-46.
Gafni Y, Zilberman Y, Turgeman G, Apparailly F, Yotvat H, Galun E, Gazit Z, Jorgensen C, Gazit D. 2004. Gene Therapy Platform for Bone Regeneration using Exogenously Regulated, AAV2 based, Gene Expression System. Mol Ther 9:587-95.
Wald O, Pappo O, Safadi R, Dagan-Berger M, Beider K, Wald H, Franitza S, Weiss I, Avniel S, Hanna J, Zamir G, Eid A, Mandelboim O, Spengler U, Galun E, Peled A. 2004. Involvement of CXCL12/CXCR4 Pathway in Advanced Hepatitis C Virus Associated Liver Disease. Eur J Immunol 34:1164-74.
Franitza S, Grabovsky V, Wald O, Weis I, Beider K, Dagan M, Darash-Yahana M, Nagler A, Brocke S, Galun E, Alon R, Peled A. 2004. Differential usage of VLA-4 and CXCR4 by CD3+CD56+ NK T and CD56+CD16+ NK cells regulates their interaction with endothelial cells. Eur J Immunology 34:1333-41.
Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R, Kasem S, Galun E, Peled A. 2004. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J 18:1240-2.
Matouk I, Ayesh B, Schneider,T, Ayesh S, Ohana P, de-Groot N, Hochberg A, Galun E. 2004. Oncofetal splice-pattern of the human H19 gene. Biochem Biophys Res Commun 318:916-9.
Condiotti R, Curran MA, Nolan GP, Giladi H, Ketzinel-Gilad M, Gross E, Galun E. 2004. Prolonged liver-specific transgene expression by a non-primate lentiviral vector. Biochem Biophys Res Commun 320:998-1006.
Felig Y, Almogy, G, Galun E, Ketzinel-Gilad M. 2004. A hepatocellular carcinoma cell line producing mature hepatitis B viral particles. Biochem Biophys Res Commun 321:269-74.
Rivo J, Zeira E, Galun E, Matot I. 2004. Activation of A3 adenosine receptors attenuates lung Injury following in-vivo reperfusion. Anesthesiology 101:1153-1159.
Rivo J, Zeira E, Galun E, Matot I. 2004. Activation of A3 adenosine receptor provides lung protection against ischemia-reperfusion injury associated with reduction in apoptosis. Am J Transplantation 4:1941-8.
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. 2004. NF-kappaB functions as a tumor promoter in inflammation-associated cancer. Nature 43:461-66.
Wald O, Pappo O, Ari ZB, Azzaria E, Weiss ID, Gafnovitch I, Wald H, Spengler U, Galun E, Peled A. 2004. The CCR5Delta32 allele is associated with reduced liver inflammation in hepatitis C virus infection. Eur J Immunogenet 31:249-52.
Iris B, Zilberman Y, Zeira E, Galun E, Honigman A, Turgeman G, Clemens T, Gazit Z, Gazit D. 2003. Molecular imaging of the skeleton: Quantitative real time bioluminescence monitoring gene expression in repair and development. J Bone Mineral Research18:570-8.
Gropp M, Itsykson P, Singer O, Ben-Hur T, Reinhartz E, Galun E, Reubinoff BE. 2003. Stable genetic modification of human embryonic stem cells by lentiviral vectors. Molecular Therapy 7:281-7.
Mitchell LA, Galun E. 2003. Rectal immunization of mice with hepatitis A vaccine induces a strong systemic and local immune responses that are superior to those elicited by parenteral immunization. Vaccine 21:1527-38.
Beider K, Nagler A, Wald O, Franitza S, Dagan-Berger M, Wald H, Giladi H, Brocke S, Hanna J, Mendelbaum O, Darash-Yahana M, Galun E, Peled A. 2003. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood 102:1951-8.
Zeira E, Manevitch A, Khatchatouriants A, Pappo O, Hyam E, Tavor E, Honigman A, Lewis A, and Galun E. 2003. Femtosecond infrared laser - an efficient and safe in vivo gene delivery system for prolonged expression. Mol Ther 8:342-50.
Giladi H, Ketzinel-Gilad M, Rivkin L, Felig Y, Nussbaum O, Galun E. 2003. Small Interfering RNA Inhibits HBV Replication in Mice. Mol Ther 8:769-76.
Research group
Imad, Matouk, M.Sc. (Student) Phone: 658-5456
Israel, Ariel (Ph.D. student)
Levy, Carol, B.Sc. (Technician)
Ovin, Elina, B.Sc.
Yodvat, Hagit
Zeira, Evelyne, B.Sc. (investigator) Phone: 677-8782
Zur-Levy, Galit (Ph.D. Student)
Collaborators
Gideon Zamir, MD (Department of Surgery): Development of novel therapeutic approaches to prolong adenovirus gene expression in hepatocytes through the inhibition of topoisomerase I activity, in vitro and in vivo.
Yoram Wiess, MD (Department of Anesthesiology): The role and potential clinical use of HSP70 expression in severe acute lung injury (ARDS).
Alik Honigman (Department of Virology, Hadassah-Hebrew University Medical School): The role of CREB on the growth of hepatocellular carcinoma in normoxic and hypoxic conditions.
Tamar Sela MD and Yevgeni Libson MD (Department of Radiology): Assessment of the anti tumor effect of NDV through the use of different imaging technologies.
Iri Libergal, MD, Shaul Beit, MD (Department of Orthopedics and Dan Gazit DMD (Hadassah-Hebrew University School of Dentistry): The use of human mesenchymal stem cells for the correction of completed fractures.
Ariella Oppenhim, PhD (Department of Hematology): Assessment of the SV40 gene delivery vehicle for liver directed gene targeting.
Idit Matot, MD (Department of Anesthesiology) and Antoni Varshtending, MD (Department of Radiology): Development new gene targeting systems to the liver for naked DNA delivery.
Riffat Safadi MD (Department of Medicine): Assessing the potential use of nucleic acids against liver fibrosis in a mouse CCl4 model.
Daniel Shouval, MD, Riffat Safadi MD and Yaffa Ashur, MD, (Department of Medicine) and Shlomo Dagan, PhD Neil Greham, PhD (XTLbio Ltd): Conducting a phase II clinical study to assess the use of two human monoclonal antibodies against HBV to prevent re-infection in liver transplant patients with pre-LTx HBV infection.
Gideon Zamir, MD and Ahmed Eid, MD (Department of Surgery) Riffat Safadi, MD (Department of Medicine) and Shlomo Dagan, PhD, Neil Greham, PhD (XTLbio Ltd): Conducting a phase II clinical study to assess the use of human monoclonal antibodies against HCV to prevent re-infection in liver transplant patients with pre-LTx HCV infection.
David Enk, MD (Department of Dermatology) Shlomo Dagan, PhD, Neil Greham, PhD (XTLbio Ltd): Conducting a clinical study to assess the use of human monoclonal antibodies against HCV in chronic HCV infection patients with dermatologic abnormalities.
Orit Pappo, MD ( Department of Pathology): Determination of the association of chronic liver inflammatory process and oxidative stress to the development of hepatocellular carcinoma.
Shlomo Dagan, PhD (XTLbio Ltd): Assessment of the anti HBV and HCV effects of human monoclonal antibodies against both in vitro and in vivo in the Trimera model.
Amos Panet, PhD and Zichria Rones, PhD (Department of Virology, Hadassah-Hebrew University Medical School): Assessment of the anti tumor effect of the NDV HUJ strain.
RESEARCH SUMMARY
The objective of my group is to develop new therapeutic approaches for liver related diseases. The general therapeutic modality that we selected is gene therapy to be applied for the various target diseases. The target diseases include chronic inflammation, monogenetic diseases and cancer. Our studies include basic research investigations to unfold the molecular and cellular mechanisms of maladies as well as the development of new scientific tools and therapeutic avenues.
Naked DNA delivery: The most significant obstacle in gene therapy is the development of a simple, efficient, and low cost gene delivery method with minute side-effects. Currently these are unmet objectives. Until now, gene therapy in in vitro and in vivo animal studies have proved its efficacy and in some cases in the most profound way. Furthermore, single clinical studies have also proved that it could reverse a clinical genetic phenotype. However, the major obstacle in all cases is associated with the delivery method. Up until now, most clinical studies treating over 7,000 patients have applied viral vectors. These vehicles encounter numerous disadvantages, including the augmentation of the immune response against the transgene or the activation on oncogenes in transduced cells, resulting in the short-term expression or the development of unwarranted maladies, respectively.
We are developing a new approach for the delivery of naked DNA directed to the liver. The current studies are conducted in large animals and we are showing promising preliminary results. Furthermore, we are also studying various methods for site specific integration of naked DNA into primary hepatocytes.
The studies on naked DNA to the liver are performed by Evelyne Zeira with the collaboration of Idit Matot (Department of Anesthesiology), Antoni Varshtending (Department of Radiology) and Gidon Zamir (Department of Surgery).
Feline Immunodeficiency Virus (FIV) Vector for liver directed gene delivery: A major problem in gene therapy delivery vehicles is the short-term gene expression after transduction. One method to overcome this hurdle is to use viral delivery systems that are able to integrate their genetic payload of the viral vector into the host cell genome. The advantage of the lentivirus, e.g. HIV vectors is the ability to transduce non-dividing cells, such as hepatocytes. However, the use of an HIV vector can cause public resentment. The FIV infects domestic cats in a relatively high percentage of cases.. The disease in cats does not spread to humans. We have adopted the FIV vector to study its gene delivery potential to hepatocytes in vitro and in vivo.
The assessment of the FIV vector for liver directed gene delivery is conducted by Reba Condiotti. These studies are performed in close collaboration with Ela Shai, Amos Panet (Hadassah-Hebrew University Medical School), Yaakov Palmon (Hadassah-Hebrew University School of Dentistry), Michel Curran (Stanford University), Gary Nolan (Stanford University), Hilla Giladi , Mali Ketzinel-Gilad, Eitan Gross (Department of Pediatric Surgery), Itzchak Marmari (Hadassah-Hebrew University School of Dentistry), Bruce Baum (DINIH) and Idit Segal (Department of Pediatrics).
Laser beam gene transduction (LGBT): We have developed a special laser beam energy source to enhance the entrance and expression of a transgene into the muscle tissue. The advantage of this method is that it is clinically acceptable; the disadvantage is that, under current conditions, the expression is lower than that following electroporation. This approach was developed for the treatment of chronic anemia which is associated with several conditions such as chronic renal failure, chronic infections and malignancies. This study is conducted by Evelyne Zeira in collaboration with Yitzchak Chemo, MD, Itay Chovers, MD and Aaron Lewis, PhD (Department of Ophthalmology).
Hepatitis vaccination: The first generation of vaccines in transgenic plants reported so far described only the expression of single proteins or short peptides. Our new method of vaccine development (second generation) through the production of viral-like particles in edible crops is being studied. Mali Ketzinel-Gilad and Esra Galun (Weizmann Institute) had developed 70 lines of HAV transgenic tomato plants expressing the HAV transgene, and possibly a viral particle in the tomato fruit. The results of this study revealed an immunological response of mice to this edible vaccine. Simultaneously, Leslie Mitchell has assessed the potential vaccination against HAV in mice through the rectal route. Interestingly, the mice responses induced local and systemic responses, specifically against HAV. In collaboration with investigators from Biopharmaceuticals Company, we are currently generating transgenic plants expressing HCV-derived proteins for the future assessment of this approach and for the potential development of a preventive and possibly therapeutic vaccine.
Gene therapy to hepatitis B and hepatitis C virus infections: HBV and HCV are both infectious agents with a significant health care burden for humans causing chronic diseases. The current treatments for both are not satisfactory, and for HCV there is no available vaccine and it does not seem that there will be one in the near future. We are developing various gene therapy approaches to tackle these maladies. One of the major barriers in the assessment of any antiviral strategy would be in vitro and in vivo models. In the past, in collaboration with Yaie Raisner (Weizmann Institute of Science) and Shlomo Dagan (XTLbio Ltd), we have developed a small animal model for both viruses, the Trimera system. Currently we are in the process of developing a simpler model in collaboration with XTLbio Ltd. The studies are aimed to develop gene therapy approaches to HBV and HCV and are conducted by Hilla Giladi, Mali Ketzinel-Gilad, Mila Rivkin and Elina Khvalevfky.
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