A. Gene Therapy
B. Virus replication and viral diseases
Cancer therapy using oncolytic viruses
Our knowledge of virus replication and the ability to design and engineer through molecular biology methodologies modified viruses with affinity to cancer cells has opened an exciting new approach of cancer therapy. While, the mechanisms by which these modified viruses, termed oncolytic viruses, specifically recognize and kill cancer cells is not yet clear, encouraging clinical data of their efficacy have already been demonstrated. In our laboratory, we develop and study the mechanism of action of new oncolytic viruses. We have genetically modified to attenuate two different viruses; 1. Herpes simplex virus (HSV1), that is prevalent in human, sometime causing lip blisters, and 2. New Castle Disease Virus (NDV), a chicken virus that can also infect tumor human cells. We find that these two attenuated viruses selectively infect and kill tumor cells and tissues, such as colon carcinoma and melanoma, while normal tissues are not affected by these viruses. Extensive studies to understand the selectivity of these viruses to infect and kill the tumor tissues indicated several differences between the tumor and normal tissue that facilitate the selective viral oncolytic activity. First, differences in the composition of the extracellular matrix proteins between the normal and tumor tissue blocks oncolytic virus infection of the normal tissue, and second, over-expression of several regulatory proteins specifically in the tumor tissue induce cell killing upon oncolytic virus infection. Based on this mechanistic analysis, we further develop these oncolytic viruses for human use and the first clinical trial is in progress.
Gene therapy in solid tissues
Treatment of diseases affecting solid tissues by gene therapy means is still at an early stage of development. The main hurdles to gene therapy treatments are; poor transduction of the tissue by the vectors expressing therapeutic genes and the inability to target these vectors specifically to the diseased cells. In order to overcome these limitations, we have developed a unique experimental system with which we study the factors that govern viral vector transduction and therapeutic gene expression in the cells of a solid tissue. The experimental system is based on our expertise to grow and maintain solid tissues ex vivo for extended periods of time, to transduce the tissue with a therapeutic gene ex vivo and finally to transplant back the engineered tissue to the donor. We have applied these methodologies in the development of the “Biological pump” technology. The “Biological pump” consists of a small piece of skin that is transduced ex vivo by a viral vector expressing the Erythropoietin gene (EPO, is an hormone that stimulate red blood cell and is deficient in anemic patients). The piece of skin, engineered with the EPO gene, produces the hormone and is subsequently transplanted back to the donor to overcome the hormone deficiency and stimulate red blood cell proliferation and differentiation. This platform technology is now being applied to other hormones and therapeutic proteins.
Virus infection and spread in solid tissues
To understand the pathogenic mechanisms of disease causing viruses and to be able to apply successfully viral vectors in gene therapy applications, we need to study how viruses infect and spread in their target tissue. To this end we have studied the tropism of several viruses, Herpes Simplex Virus (HSV1), Adeno virus and lentivirus in solid tissues. We have applied for this study a unique methodology, developed in our laboratory to maintain solid tissues ex vivo in their native-three-dimension architecture for extended periods of time. Following infection of the tissue with the relevant virus, the type of cells infected in the tissue and the mechanism of virus spread from cell to cell within the tissue is analyzed. Extensive work has been done on the neuro-tropism of Herpes Simplex Virus (HSV1) in the central nervous system. The results indicated that the virus preferentially infects neuronal stem cells and early progenitor cells at specific areas of the brain tissue. The mechanisms that determine this unique viral tropism in this tissue is under investigation. This work is relevant for the understanding of viral induced diseases and for the development of new drugs against viruses. Furthermore, results of these studies would facilitate design of viral vectors for gene therapy applications, particularly in the central nervous system.
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S. Matza-Porges, E. Tavor, A. Panet, and A. Honigman (2003), Intracellular expression of a functional short peptide confers resistance to apoptosis, Experimental. Cell Res. 290: 60-67.
N. Mador, E. Braun, H. Haim, H. Ariel, A. Panet and I. Steiner (2003), Transgenic mouse with the herpes simplex virus type 1 latency- associated gene: Expression and function of the transgene, J. Virol. 77: 12421-12429.
Z. Yang, B.K. Chakrabarti, L. Xu, B. Welcher, W. Kong, K. Leung, A. Panet, J.R. Mascola, and G,J. Nabel (2004), Selective modification of variable loops alters troipsm and enhances immunogenicity of Human immuno deficiency Virus type 1 envelope. J. Virol. 78: 4029-4036.
L. Ganesh, K.Leung, K lore, R. levin, A. Panet, O. Schwartz, R. A Koup and G.J. Nabel. (2004), Infection of specific dendritic cells by CCR5-tropic human immunodeficiency virus type 1 promotes cell-mediated transmission of virus resistant to broadly neutralizing antibodies, J. Virol. 78: 11980-11987.
I. Puxeddu, A. Alian, A. M. Piliponsky, D. Ribatti, A. Panet, F. Levi-Schaffer (2005), Human periferal blood eosinophils induce angiogenesis, The Inter. J. of Biochemisrty and cell biology. 37: 628-636.
H. Haim, I. Steiner. and A.Panet (2005), Synchronized infection of cell cultures by magnetically controled virus, J.virol. 79: 622-625.
E. Hasson, Y. Slovatizky, Y. Shimoni, H. Falk, A. Panet, and E. Mitrani (2005), Solid tissues can be manipulated ex-vivo and used as vehicles for gene therapy, J. Gene Medicine 7: 261-266.
S. Matza-Porges, I. Horresh, E. Tavor, A. Panet, and A. Honigman. (2005), Expression of an anti apoptotic recombinant short peptide in mammalian cells, Apoptosis. 10: 987-996.
E. Brill-Almon, B. Stern, D. Afik, J. Kaye, N. Langer, S. Bellomo, M. Shavit, A.Pearlman, Y. Lippin, A. Panet, and N. Shani. (2005), Ex vivo transduction of human dermal tissue structures for autologous implantation production and delivery of therapeutic proteins, Mol. Ther. 12:274-282.
E. Shai, A. Palmon, A. Panet, Y. Marmary, Y. Sherman, M. A. Curran, E. Galun, R. Condiotti(2005), Prolonged transgene expression in murine salivary glands following non-primate lentiviral vector transduction, Mol. Ther. 12: 137-143.
A. Panet, E. Braun, A. Honigman, and I. Steiner. (2005), Involvement of cellular death signals in the reactivation of herpes simplex virus type 1 and lambda bacteriophage from a latent state, J. Theor. Biol. 236: 88-94.
B. K. Chakrabarti, X. Ling, Z. Y. Yang, D. C. Montefiori, A. Panet, W.P. Kong, B. Welcher, M. K. Louder, J. R. Mascola, and G. J. Nabel. (2005), Expanded breadth of virus neutralization after immunization with a multiclade envelope HIV vaccine candidate, Vaccine 16: 3434-3445.
A.I . Freeman, Z. Zakay-Rones, J, M. Gomori, E. Linetsky, L. Rasooly, E. Greenbaum, S. Rozenman-Yair, A. Panet, E. Libson, C. S. Irving, E. Galun, and T. Siegal. (2006), Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme, Mol. Ther. 13: 221-228.
Y. Hagay, J. Lahav, A. Levanon, D. Varon, A. Brill, and A. Panet. (2006), Molecular characterization of an human monoclonal antibody that interacts with a sulfated tyrosine-containing epitope of the GPIb receptor and inhibits platelet functions, Mol. Immunol. 43: 443-453.
E. Braun, T. Zimmerman, T.B. Hur, E. Reinhartz, Y. Fellig, A. Panet, and I. Steiner. (2006), Neurotropism of herpes simplex virus type 1 in brain organ cultures, J. Gen.Virol. 87:2827-37.
M. Carmo, T. Q. Faria, H. Falk, A. S. Coroadinha, M. Teixeira, O.-W. Merten, C. Gény-Fiamma, P. M. Alves, O. Danos, A. Panet, M. J. T. Carrondo, and P. E. Cruz. (2006), Relationship between retroviral vector membrane and vector stability J. Gen Virol. 87:1349-1356.
H. Haim, I. Steiner, and A. Panet. (2007), Time frames of neutraliztion during the HIV-1 entry phase as monitored in synchronously infected cell cultures, J. Virol. 3525-3534.
D. Kolodkin-Gal, G. Zamir, E. Pikarski, N. Shimony, H. Wu, Y.S. Haviv, and A. Panet. (2007), A novel system to study adenovirus tropism to normal and malignant colon tissues, Virology 357: 91-101.
Aframian, D.J., Amit, D., David, R., Shai, E., Deutsch, D., Honigman, A., Panet, A., and Palmon, A.. (2007), Reengineering salivary gland cells to enhance protein secretion for use in developing artificial salivary gland device, Tissue Eng.13:995-1001.
Kolodkin-Gal, D., Zamir, G., Edden, Y., Pikarsky, E., Pikarsky, A., Haim, H., Haviv, Y.S., and Panet. A. (2007), HSV-1 Preferentially Targets Human Colon Carcinoma: The Role of Extra-Cellular Matrix, J. Virol. 82: 999-1010.
Carmo M, Panet A, Carrondo MJ, Alves PM, Cruz PE. (2008), From retroviral vector production to gene transfer: spontaneous inactivation is caused by loss of reverse transcription capacity, J Gene Med. 10:383-391.
Kunicher N., Falk H., Yaacov B., Tzur T. and Panet A. (2008), Tropism of lentiviral vectors in skin tissue, Human Gene therapy 19: 255-266.
Yaacov B, Elihaoo E, Lazar I, Ben-Shlomo M, Greenbaum I, Panet A, Zakay-Rones Z. (2008), Selective oncolytic effect of an attenuated Newcastle disease virus (NDV-HUJ) in lung tumors, Cancer Gene Therapy 15: 795-807.
Kolodkin-Gal D, Edden Y, Hartshtark Z, Ilan L, Khalaileh A, Pikarsky AJ, Pikarsky E, Rabkin SD, Panet A, Zamir G., Herpes simplex virus delivery to orthotopic rectal carcinoma results in an efficient and selective antitumor effect, Gene Therapy. (2009) May 14. [Epub ahead of print]
Abbadessa G, et al. Panet A., Zipeto D. (2009), Unsung hero Robert C. Gallo, Science 323:206-207
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Vogel, T., Levanon, A., Werber, M., Guy, R., Panet, A. Fibrin binding domain polypeptides and uses and methods of producing same. United States Patent # 5,965,383.
Vogel, T., Levanon, A., Werber, M., Guy, R., Panet, A. Hartman J., Shaked, H. Fibrin binding domain polypeptides and uses and methods of producing same. United States Patent # 5,965,616.
Werber, M., Zeelon, E., Levanon, A., Guy, R., Goldlust, A., Rigbi, M., Panet, A., Fischer M. Production of recombinant Factor Xa inhibitor of Leech Hirudo Medicinalis. United States Patent # 5,801,017.
Vogel, T., Levanon, A., Werber, M., Guy, R., Panet, A. Hartman J., Shaked, H. Fibrin binding domain polypeptides and uses and methods of producing same. United States Patent # 5,679,320.
Vogel, T., Levanon, A., Werber, M., Guy, R., Panet, A. Fibrin binding domain polypeptides and uses and methods of producing same. United States Patent # 5,455,158.
Vogel, T., Levanon, A., Werber, M., Guy, R., Panet, A. Fibrin binding domain polypeptide and methods of producing. United States Patent # 5,270,030.
Werber, M., Zeelon, E., Levanon, A., Guy, R., Goldlust, A., Rigbi, M., Panet, A., Fischer M. Production of recombinant Factor Xa inhibitor of Leech Hirudo Medicinalis. PCT application WO 94/23709.
Garfinkel, L., Gorecki, M., Panet, A. Method of enhancing thrombolysis. PCT application WO 94/25582.
Vogel, T., Gallo, R., Browning P., Roberts, D., Panet, A. Method of inhibiting Kaposi’s sarcoma. PCT application WO 95/05190.
Panet, A., Vogel, T. New peptides useful for directing therapeutics to cancer tissues – and endothelial cells. Priority Applications: US 98154404 A 19980910; WO 98US4188A.
Panet, A., Vogel , T., Zeelon, E. New peptide(s) binding targets in organs and lymphocytes – used in the targetted delivery of toxins, anti-cancer drugs and cardiovascular agents to arteries, veins, placenta, liver. Priority Applications: US 97810074 A 19970304.
Fischer, M., Goldlust, A., Guy R., Levanon, A., Panet, A., Rigbi, M., Werber, M., Zeelon, E. DNA encoding Hirudo medicinalis Factor Xa inhibitor polypeptide-useful for producing recombinant polypeptides. Priority Applications: US 94226264 A 19940408; US 9345804 A 19930409.
Browning, P., Gallo, R., Panet, A., Roberts, D., Vogel, T. Inhibiting Kaposi’s syndrome – comprises administering Apo-lipoprotein. Priority Applications: US 93105900 A 19930812.
Garfinkel, L., Gorecki, M., Panet, A. Use of von Willebrand factor glycoprotein lb binding domain – to improve thrombolytic treatment and, in conjunction with aspirin, to prevent complications following traumatic vascular injury. Priority Applications: US 9352543 A 19930423.
Fischer, M., Goldlust, A., Guy R., Levanon, A., Panet, A., Rigbi, M., Werber, M., Zeelon, E. Recombinant Factor Xa inhibitor of Hirudo medicinalis- for treating excessive blood coagulation partic. Thrombosis, also related DNA, vectors, transformed cells and antibodies. Priority Applications: US 9345804 A 19930409.
Panet, A., Vogel, T. Compsns contg apolipoprotein E—for inhibiting proliferation of actively proliferating cells, eg tumour cells. Priority Applications: US 92928979 A 19920812.
Guy, R., Hartman J., Levanon A., Panet A., Shaked, H., Vogel, T., Werber, M. New Fibrin binding domain polypeptide(s) – useful in imaging fibrin – contg. Substances, to inhibit thrombus formation and treat wounds. Priority Applications: US 90526397 A 19900522.
Guy, R., Levanon, A., Panet, A., Vogel, T., Werber, M. Plasmids encoding polypeptide analogies of human fibronectin-expressed prods. Useful for inhibiting platelet aggregation, and thromboxane release from platelets. Priority applications: US 89345952 A 19890428.
Werber, M., Zeelon, E., Levanon, A., Guy, R., Goldlust,A., Rigbi, M., and Panet, A., Production of a recombinant factor Xa inhibitor of leech Hirudo medicinalis. EU EP0 693 925 B1
Rones-Zakay, Z., Panet, A., and Irving C. Composition and methods for treatment of cancer. PCT application WO 03/022202 A2