| Medical Degree: |
M.D., Medicine, Tokyo Medical & Dental University, 1986
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| Degree: |
Ph.D., Endocrinology / Physiology, University of California San Francisco (UCSF), 1994
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| Medical Board Certification: |
Clinical Pathology, American Board of Pathology, 1996
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| Residency: |
Laboratory Medicine, UCSF, 1995
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| Laboratory Address: |
Kasahara Lab
675 Charles E Young Drive S
MRL-1551
Campus - 701922
Los Angeles, CA 90095
UNITED STATES
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Work Phone Number:
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(310) 825-7112
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Development of Novel Strategies and Vector Systems for Gene Therapy
With few exceptions, clinical gene therapy trials have found significant shortcomings in all standard gene delivery systems and a significant lack of therapeutic efficacy, in large part due to the inability of these standard systems to achieve efficient gene delivery in vivo. We have established expertise in many of the major virus-based gene delivery vehicle ("vector") systems in current use. We are now seeking to maximize the potential for achieving successful gene therapy of diseases such as cancer by carefully selecting the appropriate therapeutic gene "payload" for existing vector systems, and by developing a new generation of gene delivery vector systems.
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Development of Novel Strategies and Vector Systems for Gene Therapy
- 1. Use of Therapeutic Genes Encoding Secreted Proteins in Standard Vector Systems: We have sought to compensate for the relatively low in vivo efficiency of conventional gene delivery vector systems by delivering genes encoding secreted proteins as therapeutic agents. Our primary model for testing this approach has been adenovirus- and lentivirus-mediated gene delivery of secreted anti-angiogenic factors such as thrombospondin-1, angiostatin, and endostatin, for treatment of cancer. In a related project, we are exploring the feasibility of using lentivirus and AAV vectors for delivery of genes encoding anti-inflammatory factors and anti-fibrogenic factors.
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2. Conditionally Replication-Competent Retrovirus Vectors for Cancer Gene Therapy: We have developed murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vectors, and have demonstrated that such vectors are capable of highly efficient replicative spread and gene delivery throughout solid tumors in vivo. Due to its natural inability to infect quiescent cells, MLV infection is selective for actively dividing tumor cells, and as this virus stably integrates into the genome of the tumor cell, RCR vectors achieve not only efficient but also persistent infection in vivo, allowing the virus to follow tumor cells even as they migrate and form metastatic foci. We have found that RCR-mediated suicide gene therapy can achieve significant tumor inhibition and prolonged survival benefit in experimental models of breast cancer, prostate cancer, glioma, and colorectal cancer.
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3. Development of Novel Adenovirus-Retroelement Hybrid Vectors: We have developed novel hybrid virus vector systems that transduce cells via a two stage, Trojan horse-type mechanism: in the first-stage, a helper-dependent adenovirus delivers all of the components necessary for in situ production of a second-stage retrovirus/lentivirus or retrotransposon in the primary target cells, and in the second-stage, the retroelements will mediate stable integration. This hybrid vector system is thus designed to combine the most advantageous characteristics of both types of vectors, being capable of efficient high level transduction in vivo via the first-stage adenovirus, as well as stable integration into the host cell genome via the second-stage retroelement.
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Nori Kasahara is a Professor in the Department of Medicine and holds joint appointments in the Department of Molecular & Medical Pharmacology and the Interdepartmental Program in Molecular Biology. He obtained his medical degree from Tokyo Medical and Dental University in 1986, and after concurrently completing both his clinical residency training in Laboratory Medicine (Clinical Pathology) in 1993 as well as his Ph.D. graduate studies in Endocrinology at the University of California San Francisco (UCSF) in 1994, he was an Assistant Professor in the Department of Pathology and Institute for Genetic Medicine at the University of Southern California until 2002. Dr. Kasahara was one of the first to demonstrate that exogenous ligand sequences could be engineered into retroviral envelopes to mediate targeted cell type-specific binding via ligand-receptor interaction, and is continuing research on the development of novel gene transfer vector systems and strategies for gene therapy of cancer and other diseases. He also serves as the Director of the Molecular Vector Core Facilities of the UCLA/CURE Digestive Disease Research Center and the Jonsson Comprehensive Cancer Center, and is currently a member of the American Society of Gene Therapy (ASGT) Scientific Committee on Viral Gene Transfer Vectors and the editorial board of Cancer Gene Therapy, and currently serves as President of the International Society for Cell & Gene Therapy of Cancer.
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Haga Kazunori, Tomioka Atsushi, Liao Chun-Peng, Kimura Takahiro, Matsumoto Hiroshi, Ohno Izumi, Hermann Kip, Logg Christopher R, Jiao Jing, Tanaka Motoyoshi, Hirao Yoshihiko, Wu Hong, Kruse Carol A, Roy-Burman Pradip, Kasahara Noriyuki PTEN knockout prostate cancer as a model for experimental
immunotherapy..
The Journal of urology.
2009; 181(1):
354-62.
Logg Christopher R, Baranick Brian T, Lemp Nathan A, Kasahara Noriyuki Adaptive evolution of a tagged chimeric gammaretrovirus:
identification of novel cis-acting elements that modulate splicing..
Journal of molecular biology.
2007; 369(5):
1214-29.
Hiraoka Kei, Kimura Takahiro, Logg Christopher R, Tai Chien-Kuo, Haga Kazunori, Lawson Gregory W, Kasahara Noriyuki Therapeutic efficacy of replication-competent retrovirus
vector-mediated suicide gene therapy in a multifocal colorectal cancer
metastasis model..
Cancer research.
2007; 67(11):
5345-53.
Guinn, B. A. Norris, J. S. Huang, L. Farzaneh, F. Kasahara, N. Deisseroth, A. B. International Society for Cell and Gene Therapy of Cancer (ISCGT) annual meeting: conference overview and introduction to the symposium papers.
Cancer Immunol Immunother.
2006;
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Kubo, S. Seleme Mdel, C. Soifer, H. S. Perez, J. L. Moran, J. V. Kazazian, H. H., Jr. Kasahara, N. L1 retrotransposition in nondividing and primary human somatic cells.
Proc Natl Acad Sci U S A.
2006; 103(21):
8036-41.
Oshikiri, T. Miyamoto, M. Hiraoka, K. Shichinohe, T. Kawarada, Y. Kato, K. Suzuoki, M. Nakakubo, Y. Kondo, S. Dosaka-Akita, H. Kasahara, N. Katoh, H. Transcriptional targeting of adenovirus vectors with the squamous cell carcinoma-specific antigen-2 promoter for selective apoptosis induction in lung cancer.
Cancer Gene Ther.
2006;
.
Dalba, C. Klatzmann, D. Logg, C. R. Kasahara, N. Beyond oncolytic virotherapy: replication-competent retrovirus vectors for selective and stable transduction of tumors.
Curr Gene Ther.
2005; 5(6):
655-67.
Wang, W. Zhu, N. L. Chua, J. Swenson, S. Costa, F. K. Schmitmeier, S. Sosnowski, B. A. Shichinohe, T. Kasahara, N. Chen, T. C. Retargeting of adenoviral vector using basic fibroblast growth factor ligand for malignant glioma gene therapy.
J Neurosurg.
2005; 103(6):
1058-66.
Stripecke, R. Kasahara, N. Retroviral and Lentiviral Vector Systems for Cancer Gene Therapy.
Gene Therapy for Cancer
2005; in press.:
.
Tai, C. K. Wang, W. J. Chen, T. C. Kasahara, N. Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival benefit in experimental glioma.
Mol Ther.
2005; 12(5):
842-51.
Wang, Y. Xie, J. Yarber, F. A. Mazurek, C. Trousdale, M. D. Medina-Kauwe, L. K. Kasahara, N. Hamm-Alvarez, S. F. Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland.
Gene Ther.
2004; 11(12):
970-81.
Nakamura, S. Nakamura, R. Shibata, K. Kobayashi, M. Sahara, N. Shigeno, K. Shinjo, K. Naito, K. Ohnishi, K. Kasahara, N. Iwaki, Y. Development of packaging cell lines for generation of adeno-associated virus vectors by lentiviral gene transfer of trans-complementary components.
Eur J Haematol.
2004; 73(4):
285-94.
Kikuchi, E. Menendez, S. Ohori, M. Cordon-Cardo, C. Kasahara, N. Bochner, B. H. Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin.
Clin Cancer Res.
2004; 10(5):
1835-42.
Koya, R. C. Weber, J. S. Kasahara, N. Lau, R. Villacres, M. C. Levine, A. M. Stripecke, R. Making dendritic cells from the inside out: lentiviral vector-mediated gene delivery of granulocyte-macrophage colony-stimulating factor and interleukin 4 into CD14+ monocytes generates dendritic cells in vitro.
Hum Gene Ther.
2004; 15(8):
733-48.
Soifer, H. S. Kasahara, N. Retrotransposon-adenovirus hybrid vectors: efficient delivery and stable integration of transgenes via a two-stage mechanism.
Curr Gene Ther.
2004; 4(4):
373-84.
Logg, C. R. Kasahara, N. Retrovirus-mediated gene transfer to tumors: utilizing the replicative power of viruses to achieve highly efficient tumor transduction in vivo.
Methods Mol Biol.
2004; 246:
499-525.
Tai, C. K. Logg, C. R. Park, J. M. Anderson, W. F. Press, M. F. Kasahara, N. Antibody-mediated targeting of replication-competent retroviral vectors.
Hum Gene Ther.
2003; 14(8):
789-802.
Wang, W. J. Tai, C. K. Kasahara, N. Chen, T. C. Highly efficient and tumor-restricted gene transfer to malignant gliomas by replication-competent retroviral vectors.
Hum Gene Ther.
2003; 14(2):
117-27.
Koya, R. C. Kasahara, N. Favaro, P. M. Lau, R. Ta, H. Q. Weber, J. S. Stripecke, R. Potent maturation of monocyte-derived dendritic cells after CD40L lentiviral gene delivery.
J Immunother.
2003; 26(5):
451-60.
Stripecke, R. Koya, R. C. Ta, H. Q. Kasahara, N. Levine, A. M. The use of lentiviral vectors in gene therapy of leukemia: combinatorial gene delivery of immunomodulators into leukemia cells by state-of-the-art vectors.
Blood Cells Mol Dis.
2003; 31(1):
28-37.
Soifer, H. Higo, C. Logg, C. R. Jih, L. J. Shichinohe, T. Harboe-Schmidt, E. Mitani, K. Kasahara, N. A novel, helper-dependent, adenovirus-retrovirus hybrid vector: stable transduction by a two-stage mechanism.
Mol Ther.
2002; 5(5 Pt 1):
599-608.
Chen, M. Kasahara, N. Keene, D. R. Chan, L. Hoeffler, W. K. Finlay, D. Barcova, M. Cannon, P. M. Mazurek, C. Woodley, D. T. Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa.
Nat Genet.
2002; 32(4):
670-5.
Logg, C. R. Logg, A. Matusik, R. J. Bochner, B. H. Kasahara, N. Tissue-specific transcriptional targeting of a replication-competent retroviral vector.
J Virol.
2002; 76(24):
12783-91.
Koya, R. C. Kasahara, N. Pullarkat, V. Levine, A. M. Stripecke, R. Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses.
Leukemia.
2002; 16(9):
1645-54.
Logg, C. R. Tai, C. K. Logg, A. Anderson, W. F. Kasahara, N. A uniquely stable replication-competent retrovirus vector achieves efficient gene delivery in vitro and in solid tumors.
Hum Gene Ther.
2001; 12(8):
921-32.
Shichinohe, T. Bochner, B. H. Mizutani, K. Nishida, M. Hegerich-Gilliam, S. Naldini, L. Kasahara, N. Development of lentiviral vectors for antiangiogenic gene delivery.
Cancer Gene Ther.
2001; 8(11):
879-89.
Logg, C. R. Logg, A. Tai, C. K. Cannon, P. M. Kasahara, N. Genomic stability of murine leukemia viruses containing insertions at the Env-3' untranslated region boundary.
J Virol.
2001; 75(15):
6989-98.
Medina-Kauwe, L. K. Maguire, M. Kasahara, N. Kedes, L. Nonviral gene delivery to human breast cancer cells by targeted Ad5 penton proteins.
Gene Ther.
2001; 8(23):
1753-61.
Lin, A. H. Kasahara, N. Wu, W. Stripecke, R. Empig, C. L. Anderson, W. F. Cannon, P. M. Receptor-specific targeting mediated by the coexpression of a targeted murine leukemia virus envelope protein and a binding-defective influenza hemagglutinin protein.
Hum Gene Ther.
2001; 12(4):
323-32.
Yoon, T. K. Shichinohe, T. Laquerre, S. Kasahara, N. Selectively replicating adenoviruses for oncolytic therapy.
Curr Cancer Drug Targets.
2001; 1(2):
85-107.
Soifer, H. Higo, C. Kazazian, H. H., Jr. Moran, J. V. Mitani, K. Kasahara, N. Stable integration of transgenes delivered by a retrotransposon-adenovirus hybrid vector.
Hum Gene Ther.
2001; 12(11):
1417-28.
Borok, Z. Harboe-Schmidt, J. E. Brody, S. L. You, Y. Zhou, B. Li, X. Cannon, P. M. Kim, K. J. Crandall, E. D. Kasahara, N. Vesicular stomatitis virus G-pseudotyped lentivirus vectors mediate efficient apical transduction of polarized quiescent primary alveolar epithelial cells.
J Virol.
2001; 75(23):
11747-54.
Chen, M. O'Toole, E. A. Muellenhoff, M. Medina, E. Kasahara, N. Woodley, D. T. Development and characterization of a recombinant truncated type VII collagen "minigene". Implication for gene therapy of dystrophic epidermolysis bullosa.
J Biol Chem.
2000; 275(32):
24429-35.
Song, Z. Powell, W. C. Kasahara, N. van Bokhoven, A. Miller, G. J. Roy-Burman, P. The effect of fibroblast growth factor 8, isoform b, on the biology of prostate carcinoma cells and their interaction with stromal cells.
Cancer Res.
2000; 60(23):
6730-6.
Sakoda, T. Kasahara, N. Hamamori, Y. Kedes, L. A high-titer lentiviral production system mediates efficient transduction of differentiated cells including beating cardiac myocytes.
J Mol Cell Cardiol.
1999; 31(11):
2037-47.
Han, X. Kasahara, N. Kan, Y. W. Ligand-directed retroviral targeting of human breast cancer cells.
Proc Natl Acad Sci U S A.
1995; 92(21):
9747-51.
Kasahara, N. Dozy, A. M. Kan, Y. W. Tissue-specific targeting of retroviral vectors through ligand-receptor interactions.
Science.
1994; 266(5189):
1373-6.
Sakamoto, S. Mori, T. Sawaki, K. Sassa, S. Suzuki, S. Sugiura, Y. Kudo, H. Kasahara, N. Nagasawa, H. Effects of danazol on DNA synthesis in rat prostate.
Prostate.
1993; 22(2):
119-24.
Sakamoto, S. Mizuno, M. Kudo, H. Suzuki, S. Kasahara, N. Sugiura, Y. Mori, T. Nagasawa, H. Suppression of mammary tumors by oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil in SHN virgin mice.
Anticancer Drugs.
1993; 4(6):
651-5.
Sakamoto, S. Kasahara, N. Kudo, H. Iwama, T. Effects of carcinogenesis on colonic thymidine kinase activity in familial adenomatous polyposis.
Carcinogenesis.
1992; 13(5):
873-6.
Sakamoto, S. Mizuno, M. Sawaki, K. Kudo, H. Kasahara, N. Suzuki, S. Mori, T. Nagasawa, H. Suppression by 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil of preneoplastic mammary hyperplastic alveolar nodule formation in SHN virgin mice.
Anticancer Res.
1992; 12(4):
1291-4.
Sakamoto, S. Hirai, H. Taga, H. Uchikoshi, T. Sunaga, T. Endo, Y. Kudo, H. Kato, T. Kasahara, N. Kuwa, K. et al., Inhibition by 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil of hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene in rats.
Anticancer Res.
1991; 11(2):
561-6.
Sakamoto, S. Hirai, H. Taga, H. Uchikoshi, T. Sunaga, T. Endo, Y. Kuwa, K. Kudo, H. Kawachi, Y. Kasahara, N. et al., Thymidine kinase and alpha-fetoprotein as biochemical markers of hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene treatment in rats.
Carcinogenesis.
1990; 11(1):
145-50.
Sakamoto, S. Kuwa, K. Tsukada, K. Sagara, T. Kasahara, N. Okamoto, R. Relative activities of thymidylate synthetase and thymidine kinase in 1,2-dimethylhydrazine-induced colon carcinomas in rats.
Carcinogenesis.
1987; 8(3):
405-8.
Sakamoto, S. Iwama, T. Ebuchi, M. Tsukada, K. Sagara, T. Kawasaki, T. Murakami, S. Kasahara, N. Kudo, H. Okamoto, R. Increased activities of thymidine kinase isozymes in human mammary tumours.
Br J Surg.
1986; 73(4):
272-3.
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