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Enhancing biological therapy through conditional regulation of protein stability

Published online by Cambridge University Press:  12 January 2010

Steve H. Thorne
Affiliation:
Departments of Surgery and Immunology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. E-mail: thornesh@upmc.edu

Abstract

The ability to externally regulate the expression or function of a gene product has proven to be a powerful tool in the study of proteins and disease in vitro, and more recently in transgenic animal models. The transfer of these technologies to regulate a therapeutic, adoptively transferred gene product in a clinical setting may provide a means to exert additional control over a large variety of therapies for many diseases, leading to increased safety and effectiveness. This could be applied to any biological therapy, including gene therapy, viral therapies, cellular therapies (such as immune cell therapies, stem cell therapies and bone marrow transplant), some vaccines and even organ transplant. A variety of systems have been used in a basic research setting to conditionally regulate the function of a protein, including control of transcription and mRNA stability, and the use of protein inhibitors. However, most of these have disadvantages for medical use, where a simple, specific, tunable, reversible and broadly applicable means to regulate protein function is needed. Recent advances in controlling the stability or function of proteins through the interaction of small-molecule effectors and fusion domains on the protein have raised the possibility that direct and highly specific external control of therapeutic protein function in humans will be feasible.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2010

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References

References

1Taylor, S.L. et al. (2007) Targeted retroviral gene delivery using ultrasound. Journal of Gene Medicine 9, 77-87CrossRefGoogle ScholarPubMed
2Jennings, G.T. and Bachmann, M.F. (2008) The coming of age of virus-like particle vaccines. Biological Chemistry 389, 521-536CrossRefGoogle ScholarPubMed
3Guo, Z.S., Thorne, S.H. and Bartlett, D.L. (2008) Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses. Biochimica et Biophysica Acta 1785, 217-231Google ScholarPubMed
4Dudley, M.E. and Rosenberg, S.A. (2007) Adoptive cell transfer therapy. Seminars in Oncology 34, 524-531CrossRefGoogle ScholarPubMed
5Penn, M.S. (2007) Cell-based gene therapy for the prevention and treatment of cardiac dysfunction. Nature Clinical Practice Cardiovascular Medicine 4 (Suppl 1), S83-88CrossRefGoogle ScholarPubMed
6Rice, J., Ottensmeier, C.H. and Stevenson, F.K. (2008) DNA vaccines: precision tools for activating effective immunity against cancer. Nature Reviews Cancer 8, 108-120CrossRefGoogle ScholarPubMed
7Thomas, K.R. and Capecchi, M.R. (1987) Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503-512CrossRefGoogle ScholarPubMed
8Bradley, A. et al. (1984) Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309, 255-256CrossRefGoogle ScholarPubMed
9Stimson, L. et al. (2009) HDAC inhibitor-based therapies and haematological malignancy. Annals of Oncology 20, 1293-1302CrossRefGoogle ScholarPubMed
10Cang, S., Ma, Y. and Liu, D. (2009) New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer. Journal of Hematology & Oncology 2, 22CrossRefGoogle ScholarPubMed
11Ryding, A.D., Sharp, M.G. and Mullins, J.J. (2001) Conditional transgenic technologies. Journal of Endocrinology 171, 1-14CrossRefGoogle ScholarPubMed
12Kuhn, R. et al. (1995) Inducible gene targeting in mice. Science 269, 1427-1429CrossRefGoogle ScholarPubMed
13Li, Y. et al. (2001) A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin. Cancer Research 61, 6428-6436Google ScholarPubMed
14Chen, Y. et al. (2001) CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Research 61, 5453-5460Google ScholarPubMed
15Mullen, J.T. and Tanabe, K.K. (2002) Viral oncolysis. Oncologist 7, 106-119CrossRefGoogle ScholarPubMed
16Kurihara, T. et al. (2000) Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen. Journal of Clinical Investigation 106, 763-771CrossRefGoogle ScholarPubMed
17Johnson, L. et al. (2002) Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agents. Cancer Cell 1, 325-337CrossRefGoogle ScholarPubMed
18Post, D.E. and Van Meir, E.G. (2003) A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 22, 2065-2072CrossRefGoogle ScholarPubMed
19Furth, P.A. et al. (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proceedings of the National Academy of Sciences of the United States of America 91, 9302-9306CrossRefGoogle ScholarPubMed
20Gossen, M. and Bujard, H. (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proceedings of the National Academy of Sciences of the United States of America 89, 5547-5551CrossRefGoogle ScholarPubMed
21Gunzburg, W.H. and Salmons, B. (1992) Factors controlling the expression of mouse mammary tumour virus. Biochemical Journal 283, 625-632CrossRefGoogle ScholarPubMed
22No, D., Yao, T.P. and Evans, R.M. (1996) Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 93, 3346-3351CrossRefGoogle ScholarPubMed
23Kelly, E.J. and Russell, S.J. (2009) MicroRNAs and the regulation of vector tropism. Molecular Therapy 17, 409-416CrossRefGoogle ScholarPubMed
24Elbashir, S.M. et al. (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498CrossRefGoogle ScholarPubMed
25Lee, R.C., Feinbaum, R.L. and Ambros, V. (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854CrossRefGoogle Scholar
26Wang, Q. et al. (2005) Small hairpin RNAs efficiently inhibit hepatitis C IRES-mediated gene expression in human tissue culture cells and a mouse model. Molecular Therapy 12, 562-568CrossRefGoogle ScholarPubMed
27Raab, R.M. and Stephanopoulos, G. (2004) Dynamics of gene silencing by RNA interference. Biotechnology and Bioengineering 88, 121-132CrossRefGoogle ScholarPubMed
28Harper, S.Q. et al. (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proceedings of the National Academy of Sciences of the United States of America 102, 5820-5825CrossRefGoogle Scholar
29Chang, K., Elledge, S.J. and Hannon, G.J. (2006) Lessons from Nature: microRNA-based shRNA libraries. Nature Methods 3, 707-714CrossRefGoogle ScholarPubMed
30Deans, T.L., Cantor, C.R. and Collins, J.J. (2007) A tunable genetic switch based on RNAi and repressor proteins for regulating gene expression in mammalian cells. Cell 130, 363-372CrossRefGoogle ScholarPubMed
31Kelly, E.J. et al. (2008) Engineering microRNA responsiveness to decrease virus pathogenicity. Nature Medicine 14, 1278-1283CrossRefGoogle ScholarPubMed
32Liu, J. et al. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807-815CrossRefGoogle ScholarPubMed
33Brown, E.J. et al. (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756-758CrossRefGoogle ScholarPubMed
34Sabatini, D.M. et al. (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35-43CrossRefGoogle Scholar
35Mayer, T.U. et al. (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971-974CrossRefGoogle Scholar
36Godl, K. et al. (2003) An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America 100, 15434-15439CrossRefGoogle ScholarPubMed
37Stankunas, K. et al. (2003) Conditional protein alleles using knockin mice and a chemical inducer of dimerization. Molecular Cell 12, 1615-1624CrossRefGoogle Scholar
38Liu, K.J. et al. (2007) Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice. Nature 446, 79-82CrossRefGoogle ScholarPubMed
39Banaszynski, L.A. and Wandless, T.J. (2006) Conditional control of protein function. Chemistry and Biology 13, 11-21CrossRefGoogle ScholarPubMed
40Banaszynski, L.A. et al. (2008) Chemical control of protein stability and function in living mice. Nature Medicine 14, 1123-1127CrossRefGoogle ScholarPubMed
41Bockamp, E. et al. (2002) Of mice and models: improved animal models for biomedical research. Physiological Genomics 11, 115-132CrossRefGoogle ScholarPubMed
42Yamada, G. et al. (1995) Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death. Development 121, 2917-2922CrossRefGoogle ScholarPubMed
43Poirier, F. and Robertson, E.J. (1993) Normal development of mice carrying a null mutation in the gene encoding the L14 S-type lectin. Development 119, 1229-1236CrossRefGoogle Scholar
44Lewandoski, M. (2001) Conditional control of gene expression in the mouse. Nature Reviews Genetics 2, 743-755CrossRefGoogle ScholarPubMed
45Godowski, P.J., Picard, D. and Yamamoto, K.R. (1988) Signal transduction and transcriptional regulation by glucocorticoid receptor-LexA fusion proteins. Science 241, 812-816CrossRefGoogle ScholarPubMed
46Eilers, M. et al. (1989) Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature 340, 66-68CrossRefGoogle ScholarPubMed
47Picard, D. (2000) Posttranslational regulation of proteins by fusions to steroid-binding domains. Methods in Enzymology 327, 385-401CrossRefGoogle ScholarPubMed
48Dohmen, R.J., Wu, P. and Varshavsky, A. (1994) Heat-inducible degron: a method for constructing temperature-sensitive mutants. Science 263, 1273-1276CrossRefGoogle ScholarPubMed
49Kanemaki, M. et al. (2003) Functional proteomic identification of DNA replication proteins by induced proteolysis in vivo. Nature 423, 720-724CrossRefGoogle ScholarPubMed
50Spencer, D.M. et al. (1993) Controlling signal transduction with synthetic ligands. Science 262, 1019-1024CrossRefGoogle ScholarPubMed
51Ho, S.N. et al. (1996) Dimeric ligands define a role for transcriptional activation domains in reinitiation. Nature 382, 822-826CrossRefGoogle ScholarPubMed
52Spencer, D.M. et al. (1996) Functional analysis of Fas signaling in vivo using synthetic inducers of dimerization. Current Biology 6, 839-847CrossRefGoogle ScholarPubMed
53Pruschy, M.N. et al. (1994) Mechanistic studies of a signaling pathway activated by the organic dimerizer FK1012. Chemistry and Biology 1, 163-172CrossRefGoogle ScholarPubMed
54Hay, N. and Sonenberg, N. (2004) Upstream and downstream of mTOR. Genes and Development 18, 1926-1945CrossRefGoogle ScholarPubMed
55Rivera, V.M. et al. (1996) A humanized system for pharmacologic control of gene expression. Nature Medicine 2, 1028-1032CrossRefGoogle ScholarPubMed
56Otto, K.G. et al. (2001) Cell proliferation through forced engagement of c-Kit and Flt-3. Blood 97, 3662-3664CrossRefGoogle ScholarPubMed
57Hentges, K.E. et al. (2001) FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proceedings of the National Academy of Sciences of the United States of America 98, 13796-13801CrossRefGoogle ScholarPubMed
58Liberles, S.D. et al. (1997) Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. Proceedings of the National Academy of Sciences of the United States of America 94, 7825-7830CrossRefGoogle ScholarPubMed
59Bayle, J.H. et al. (2006) Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chemistry and Biology 13, 99-107CrossRefGoogle ScholarPubMed
60Banaszynski, L.A. et al. (2006) A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell 126, 995-1004CrossRefGoogle ScholarPubMed
61Maynard-Smith, L.A. et al. (2007) A directed approach for engineering conditional protein stability using biologically silent small molecules. Journal of Biological Chemistry 282, 24866-24872CrossRefGoogle ScholarPubMed
62Herm-Gotz, A. et al. (2007) Rapid control of protein level in the apicomplexan Toxoplasma gondii. Nature Methods 4, 1003-1005CrossRefGoogle ScholarPubMed
63Armstrong, C.M. and Goldberg, D.E. (2007) An FKBP destabilization domain modulates protein levels in Plasmodium falciparum. Nature Methods 4, 1007-1009CrossRefGoogle ScholarPubMed
64Thorne, S.H., Hermiston, T. and Kirn, D. (2005) Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects. Seminars in Oncology 32, 537-548CrossRefGoogle ScholarPubMed
65Kirn, D.H. and Thorne, S.H. (2009) Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nature Reviews Cancer 9, 64-71CrossRefGoogle ScholarPubMed
66Kirn, D.H. et al. (2007) Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Medicine 4, e353CrossRefGoogle ScholarPubMed
67Thorne, S.H. et al. (2007) Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. Journal of Clinical Investigation 117, 3350-3358CrossRefGoogle ScholarPubMed
68Cress, D.E. (2008) The need for regulatable vectors for gene therapy for Parkinson's disease. Experimental Neurology 209, 30-33CrossRefGoogle ScholarPubMed
69Komita, H. et al. (2009) Conditional interleukin-12 gene therapy promotes safe and effective antitumor immunity. Cancer Gene Therapy 16, 883-891CrossRefGoogle ScholarPubMed
70Iuliucci, J.D. et al. (2001) Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers. Journal of Clinical Pharmacology 41, 870-879CrossRefGoogle ScholarPubMed
71Berger, C. et al. (2004) Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model. Blood 103, 1261-1269CrossRefGoogle Scholar
72Roth, J.A. (2006) Adenovirus p53 gene therapy. Expert Opinion on Biological Therapy 6, 55-61CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The Tom Wandless laboratory at Stanford University, USA (which pioneered the use of degradation domains):

Banaszynski, L.A. et al. (2008) Chemical control of protein stability and function in living mice. Nature Medicine 14, 1123-1127CrossRefGoogle ScholarPubMed
Banaszynski, L.A. et al. (2008) Chemical control of protein stability and function in living mice. Nature Medicine 14, 1123-1127CrossRefGoogle ScholarPubMed