Gene Therapy Bibliography Meaning


Gene transfer within the cardiovascular system was first demonstrated in 1989 yet, despite extensive basic-science and clinical research, unequivocal benefit in the clinical setting remains to be demonstrated. Potential reasons for this include the fact that recombinant viral vectors, used in the majority of clinical studies, have inherent problems with immunogenicity that are difficult to circumvent. Attention has turned therefore to plasmid vectors, which possess many advantages over viruses in terms of safety and ease of use, and many clinical studies have now been performed using non-viral technology. This review will provide an overview of clinical trials for cardiovascular disease using plasmid vectors, recent developments in plasmid delivery and design, and potential directions for this modality of gene therapy.

Plasmids, Gene therapy, Cardiovascular disease

1. Introduction

Despite impressive therapeutic developments, cardiovascular disease is the most common cause of mortality in the developed world; an ongoing need remains for new treatments. Since the first demonstration of vascular gene transfer in 1989,1 gene therapy has been heralded as an imminent addition to the Cardiologist's armamentarium. Cardiovascular pathologies represent the second-most popular target for clinical gene therapy. Recombinant viruses have been used for gene transfer in most clinical studies, adenovirus being employed most frequently.2 Beneficial effects of adenovirus-mediated gene transfer have been limited, however,2 due in part at least to the inflammatory responses and limited duration of transgene expression elicited by adenoviruses. The potential for serious adverse outcomes following viral vector administration has already been realized in the death of Jesse Gelsinger in a Phase 1 trial, attributed to an innate immune response to the delivered virus,3 and in the development of T-cell leukaemias resulting from vector integration in proximity to proto-oncogenes in two out of 10 patients in a trial of gammaretrovirus-mediated treatment of X-linked severe combined immunodeficiency.4

Non-viral vectors offer less potential hazard than viruses and numerous preclinical studies have demonstrated successful non-viral therapeutic gene transfer to cardiovascular tissues. Several clinical trials have been completed, some showing a suggestion of clinical benefit. We will provide an overview of these clinical trials followed by a discussion of recent developments in plasmid DNA (pDNA) technology and possible future directions for plasmid-mediated cardiovascular gene therapy.

2. Plasmids as gene therapy vectors

Plasmids represent the simplest form of vector for transport of DNA into the cell nucleus. Consisting of a circular, double-stranded DNA molecule varying in size from <1000 to >200 000 bp, they are found in virtually all bacterial species where they typically encode proteins engendering antibiotic resistance. A gene therapy plasmid is represented symbolically in Figure 1. It contains a gene for antibiotic resistance regulated by a prokaryotic promoter; a prokaryotic origin of replication supporting plasmid propagation, and an expression cassette containing a promoter to initiate the transcription of the transgene encoding the therapeutic protein, the transgene itself, and a polyadenylation signal, required for the nuclear export of the mRNA. Most plasmids contain only one transgene, but polycistronic expression cassettes can encode multiple proteins and, with no size limit, plasmids may contain multiple expression cassettes.

Figure 1

A typical plasmid for gene therapy. The multiple cloning site (MCS) contains several commonly used restriction endonuclease recognition sites, simplifying transgene insertion.

Figure 1

A typical plasmid for gene therapy. The multiple cloning site (MCS) contains several commonly used restriction endonuclease recognition sites, simplifying transgene insertion.

Compared with recombinant viruses, plasmids are simple to construct and easily propagated in large quantities. They also possess an excellent safety profile, with virtually no risk of oncogenesis (as genomic integration is very inefficient) and relatively little immunogenicity. Plasmids have a very large DNA packaging capacity and can accommodate large segments of genomic DNA. They are easy to handle, remaining stable at room temperature for long periods of time (an important consideration for clinical use). The main limitation with plasmids is poor gene transfer efficiency.5 Viruses have evolved complex mechanisms to facilitate cell entry and nuclear localization. Wild-type plasmids lack these mechanisms;5 however, developments in delivery methods and plasmid construction may address this shortcoming; some such developments will be discussed later. Given the potential benefits, plasmid-mediated gene therapy represents a more attractive option in many respects than viral gene therapy for cardiovascular applications.

3. Clinical studies of plasmid-mediated cardiovascular gene therapy

The following sources do not necessarily reflect the Center's positions or values. These sources, however, are excellent resources for familiarizing oneself with all sides of the relevant issues.

Genetics (General) | Genetic Determinism | Genetics Law & Public Policy | Intellectual Property & Patenting of Human Genes/Tissues | Genetic Engineering & Gene Therapy | Genetic Testing and Screening | Reproductive Genetics (Reprogenetics)

Genetics (General)

  • Andrews, Lori, Maxwell Mehlman, and Mark Rothstein. Genetics: Ethics, Law and Policy. 4th ed. Eagan, MN: West Academic, 215.
  • Atkinson, Paul, Peter Glasner, and Helen Greenslade, eds. New Genetics, New Identities. New York: Routledge, 2007.
  • Barash, Carol Isaacson. Just Genes: The Ethics of Genetic Technologies. Westport, CT: Praeger, 2007.
  • Berliner, Janice. Ethical Dilemmas in Genetics and Genetic Counseling: Principles through Case Scenarios. Oxford University Press, 2014.
  • Blackford, Russell. Humanity Enhanced: Genetic Choice and the Challenge for Liberal Democracies. Basic Bioethics. Cambridge, MA: MIT Press, 2014.
  • Boesky, Amy, ed. The Story Within: Personal Essays on Genetics and Identity. Baltimore: The Johns Hopkins University Press, 2013.
  • Bunton, Robin and Alan Petersen, eds. Genetic Governance: Health, Risk and Ethics in a Biotech Era. New York: Routledge, 2005.
  • Burley, Justine, ed. The Genetic Revolution and Human Rights. New York: Oxford University Press, 1999.
  • Burley, Justine, and John Harris, eds. A Companion to Genethics. Malden, MA: Blackwell, 2002.
  • Condit, Celeste Michelle. The Meanings of the Gene: Public Debates about Human Heredity. Madison: University of Wisconsin Press, 1999.
  • Corrigan, Oonagh. Genetic Databases: Socio-Ethical Issues in the Collection and Use of DNA. New York: Routledge, 2004.
  • Deane-Drummond, Celia. Genetics and Christian Ethics. New York: Cambridge University Press, 2006.
  • Deane-Drummond, Celia, Robin Grove-White, and Bronislaw Szerszynski. Reordering Nature: Theology, Society and the New Genetics. New York: T&T Clark, 2003.
  • DeGrazia, David. Creation Ethics: Reproduction, Genetics, and Quality of Life. Reprint ed. Oxford University Press, 2014.
  • Duster, Troy. Backdoor to Eugenics. 2nd ed. New York: Routledge, 2003. 
  • Gehring, Verna V., ed. Genetic Prospects: Essays on Biotechnology, Ethics, and Public Policy. Lanham, MD: Rowman & Littlefield, 2004.
  • Hashiloni-Dolev, Yael. A Life (Un)worthy of Living: Reproductive Genetics in Israel and Germany. Dordrecht, Netherlands: Springer, 2007.
  • Häyry, Matti. Rationality and the Genetic Challenge: Making People Better? New York: Cambridge University Press, 2010.
  • Hubbard, Ruth, and Elijah Wald. Exploding the Gene Myth. Boston: Beacon, 1999.
  • Jasanoff, Sheila, ed. Reframing Rights: Bioconstitutionalism in the Genetic Age. Cambridge, MA: MIT Press, 2011.
  • Jersild, Paul. The Nature of Our Humanity: The Ethics of Genetics and Biotechnology. Minneapolis: Fortress Press, 2009.
  • Kevles, Daniel. In the Name of Eugenics: Genetics and the Uses of Human Heredity. New York: Harvard University Press, 1995.
  • Kilner, John F., Rebecca D. Pentz, and Frank E. Young, eds. Genetic Ethics: Do the Ends Justify the Genes? Grand Rapids: Eerdmans, 1997.***
  • Kitcher, Philip. The Lives to Come: The Genetic Revolution and Human Possibilities. New York: Touchstone, 1996.
  • Langlois, Adèle. Negotiating Bioethics: The Governance of UNESCO’s Bioethics Program. New York: Routledge, 2013.
  • Lee, Kee kok. Philosophy and Revolutions in Genetics: Deep Science and Deep Technology. New York: Palgrave Macmillan, 2003.
  • Nelkin, Dorothy, and M. Susan Lindee. The DNA Mystique: The Gene as a Cultural Icon. Ann Arbor, MI: University of Michigan Press, 2004.
  • Paul, Diane B., and Jeffrey P. Brosco. The PKU Paradox: A Short History of a Genetic Disease. Johns Hopkins Biographies of Disease. Baltimore: Johns Hopkins University Press, 2013.
  • Peterson, James C. Genetic Turning Points: The Ethics of Human Genetic Intervention. Grand Rapids: Eerdmans, 2001.
  • Shannon, Thomas A., ed. Genetics: Science, Ethics, and Public Policy: Readings in Bioethics. Lanham, MD: Rowman & Littlefield, 2005.
  • Stern, Alexandra. Telling Genes: The Story of Genetic Counseling in America. Baltimore: Johns Hopkins University Press, 2012.
  • Wertz, Dorothy C., and John C. Fletcher. Genetics and Ethics in Global Perspective. Dordrecht, Netherlands: Springer, 2004.
  • Yashon, Ronnee and Michael Cummings. Human Genetics and Society. 2nd ed. Pacific Grove, CA: Brooks Cole, 2011.

Out of Print

  • Andrews, Lori B. Future Perfect. New York: Columbia University Press, 2001.
  • Cahill, Lisa Sowle.  Genetics, Theology, and Society: An Interdisciplinary Conversation. New York: Crossroad, 2005.***
  • Donovan, Aine and Ronald M. Green, eds. The Human Genome Project in College Curriculum: Ethical Issues and Practical Strategies. Lebanon, NH: Dartmouth College Press, 2008.
  • Harris, John. Clones, Genes, and Immortality: Ethics and the Genetic Revolution. New York: Oxford University Press, 1998.
  • Monsen, Rita Black. Genetics and Ethics in Health Care: New Questions in the Age of Genomics Health. Silver Spring, MD: American Nurses Association, 2008.
  • Monsour, Daniel, ed. Ethics and the New Genetics: An Integrated Approach. Toronto: University of Toronto Press, 2007.
  • Murphy, Timothy, and Marc A. Lappe, eds. Justice and the Human Genome Project. Berkeley: University of California Press, 1994.
  • Nelson, J. Robert. On the New Frontiers of Genetics and Religion. Grand Rapids: Eerdmans, 1994.
  • Parker, L.S., and Rachel A. Ankeny, eds. Mutating Concepts, Evolving Disciplines: Genetics, Medicine, and Society. Norwell, MA: Springer, 2002. (e-book edition available)
  • Peters, Ted. Genetics: Issues of Social Justice. Cleveland: Pilgrim, 1998.
  • Peters, Ted. Playing God: Genetic Determinism and Human Freedom. New York: Routledge, 1997.
  • Rothman, Barbara Katz. Genetic Maps and Human Imaginations: The Limits of Science in Understanding Who We Are. New York: W.W. Norton, 1998.
  • Song, Robert. Human Genetics: Fabricating the Future. Cleveland: Pilgrim, 2002.***

Genetic Determinism

  • Buchanan, Allen, Dan W. Brock, Norman Daniels, and Daniel Wikler. From Chance to Choice: Genetics and Justice. New York: Cambridge University Press, 2000.
  • Clark, William R. and Michael Grunstein. Are We Hardwired? The Role of Genes in Human Behavior. New York, Oxford University Press, 2000.
  • Keller, Evelyn Fox. The Century of the Gene. Cambridge, MA: Harvard University Press, 2001.
  • Maheu, Louis and Roderick A. MacDonald, eds. Challenging Genetic Determinism: New Perspectives on the Gene in Its Multiple Environments. Canada: McGill-Queen's University Press, 2011.
  • Parens, Erik, Audrey R. Chapman, and Nancy Press, eds. Wrestling with Behavioral Genetics: Science, Ethics, and Public Conversation. Baltimore: Johns Hopkins University Press, 2008.

Out of Print

  • Peters, Ted. Playing God? Genetic Determinism and Human Freedom. New York: Routledge, 2003.

Genetics Law & Public Policy

For relevant materials see the Public Policy Bibliography, particularly the "Genetics & Public Policy" Section.

Intellectual Property & Patenting of Human Genes/Tissues

  • Koepsell, David. Who Owns You? The Corporate Gold Rush to Patent Your Genes. Malden, MA: Blackwell, 2009.
  • Mills, Oliver. Biotechnological Inventions: Moral Restraints and Patent Law. Burlington, VA: Ashgate, 2005.
  • Resnik, David B. Owning the Genome: A Moral Analysis of DNA Patenting. Albany, NY: State University of New York Press, Albany, 2004.
  • Rimmer, Matthew and Alison McLennan, eds. Intellectual Property and Emerging Technologies. Northampton, MA: Edward Elgar Publishing, Inc., 2012.
  • Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Broadway Paperbacks, 2010.
  • Van Overwalle, Geertrui. Gene Patents and Collaborative Licensing Models: Patent Pools, Clearinghouses, Open Source Models and Liability Regimes. New York: Cambridge University Press, 2009.

Out of Print

  • Magnus, David, Arthur L. Caplan, and Glenn McGee, eds. Who Owns Life? Amherst, NY: Prometheus Books, 2002.

Genetic Engineering & Gene Therapy

See related materials in the Biotechnology, Emerging Technology, and Human Enhancement Bibliographies.

  • Baillie, Harold W. and Timothy K. Casey. Is Human Nature Obsolete? Genetics, Bioengineering, and the Future of the Human Condition. Cambridge, MA: MIT Press, 2005.
  • Berry, Roberta. The Ethics of Genetic Engineering. New York: Routledge, 2007.
  • Cole-Turner, Ronald, ed. Design and Destiny: Jewish and Christian Perspectives on Human Germline Modification. Cambridge, MA: MIT Press, 2008.
  • Edmonds, Matt. A Theological Diagnosis: A New Direction on Genetic Therapy, ‘Disability’ and the Ethics of Healing. Philadelphia: Jessica Kingsley Publishers, 2011.
  • Evans, John H. Playing God? Human Genetic Engineering and the Rationalization of Public Bioethical Debate. Chicago: The University of Chicago Press, 2002.
  • Flaman, Paul. Genetic Engineering: Christian Values and Catholic Teaching. Mahwah, NJ: Paulist Press, 2002. ***
  • Green, Ronald M. Babies by Design: The Ethics of Genetic Choice. New Haven, CT: Yale University Press, 2007.
  • LeVine III, Harry. Genetic Engineering. 2nd ed. Santa Barbara: ABC-CLIO Inc., 2006.
  • Mehlman, Maxwell J. Transhumanist Dreams and Dystopian Nightmares: The Promise and Peril of Genetic Engineering. Baltimore: The Johns Hopkins University Press, 2012.
  • Miah, Andy. Genetically Modified Athletes: Biomedical Ethics, Gene Doping and Sport. London: Routledge, 2004.
  • Nossal, G. J. V. and Ross L. Coppel. Reshaping Life: Key Issues in Genetic Engineering. New York: Cambridge University Press, 2002.
  • Rasko, John, Gabrielle O'Sullivan, and Rachel Ankeny, eds. The Ethics of Inheritable Genetic Modification: A Dividing Line? New York: Cambridge University Press, 2006.
  • Reiss, Michael J. and Roger Straughan. Improving Nature? The Science and Ethics of Genetic Engineering. United Kingdom: Cambridge University Press, 2001.
  • Sandel, Michael J. The Case against Perfection: Ethics in the Age of Genetic Engineering. Cambridge, MA: Belknap, 2007.
  • Schneider, Angela J., and Theodore Friedmann, eds. Gene Doping in Sports: The Science and Ethics of Genetically Modified Athletes. San Diego: Academic, 2006.
  • Stock, Gregory. Redesigning Humans: Our Inevitable Genetic Future. New York: Houghton Mifflin, 2002.

Out of Print

  • Boylan, Michael, and Kevin Brown. Genetic Engineering: Science and Ethics on the New Frontier. Upper Saddle River, NJ: Prentice Hall, 2001.
  • Coors, Marilyn E. The Matrix: Charting an Ethics of Inheritable Genetic Alteration. Lanham, MD: Rowman & Littlefield, 2002.
  • Dann, Jack, and Gardner R. Dozois, eds. Clones: Nine Tales of Genetic Engineering and Its Impact on Tomorrow. New York: Ace, 1997. (e-book edition available)
  • Demy, Timothy J. and Gary P. Stewart, eds. Genetic Engineering: A Christian Repsonse: Crucial Considerations for Shaping Life. Grand Rapids: Kregel, 1999. ***
  • Gordon, Jon W. The Science and Ethics of Engineering the Human Germ Line: Mendel's Maze. Hoboken, NJ: Wiley-Liss, Inc., 2003.
  • Palmer, Julie Gage, and LeRoy Walters. The Ethics of Human Gene Therapy. New York: Oxford University Press, 1997.
  • Shannon, Thomas A. Made in Whose Image: Genetic Engineering and Christian Ethics. New York: Humanity Books, 1999.***
  • Stock, Gregory, and John Campbell, eds. Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children. New York: Oxford University Press, 2000.

Genetic Testing & Screening

See related materials in the Disability Ethics and Reproductive Ethics Bibliographies.

  • Baily, Mary Ann and Thomas H. Murray, eds.  Ethics and Newborn Genetic Screening: New Technologies, New Challenges. Baltimore: John Hopkins University Press, 2009.
  • Chadwick, Ruth F., Darren Shickle, H.A. Ten Have, and Urban Wiesing, eds. The Ethics of Genetic Screening. The Netherlands: Kluwer Academic, 2010.
  • Klizman, Robert. Am I My Genes? Confronting Fate and Family Secrets in the Age of Genetic Testing. New York: Oxford University Press, 2012.
  • Raz, Aviad E. Community Genetics and Genetic Alliances: Eugenics, Carrier Testing, and Networks of Risk. New York: Routledge, 2010.
  • Sharpe, Neil F., and Ronald F. Carter. Genetic Testing: Care, Consent and Liability. Hoboken, NJ: John Wiley & Sons, 2006.
  • Skene, Loane and Janna Thompson, eds. The Sorting Society: The Ethics of Genetic Screening and Therapy. New York: Cambridge University Press, 2008.
  • Valverde, Carlos. Genetic Screening of Newborns: An Ethical Inquiry. New York: Nova Science Publishers, 2010.

Out of Print

Reproductive Genetics (Reprogenetics)

See related materials in the Disability Ethics, Human Enhancement, and Reproductive Ethics Bibliographies.

  • Chadwick, Ruth, ed. Ethics, Reproduction and Genetic Control. 2nd ed. New York: Routledge, 1994.
  • Davis, Dena S. Genetic Dilemmas: Reproductive Technology, Parental Choices, and Children's Futures. 2nd ed. New York: Oxford University Press, 2009.
  • Glover, Jonathan.  Choosing Children: Genes, Disability, and Design. New York: Oxford University Press, 2006. 
  • Knowles, Lori P. and Gregory K. Kaebnick, eds.  Reprogenetics: Law, Policy and Ethical Issues.  Baltimore: John Hopkins University Press, 2007.
  • Gavaghan, Colin. Defending the Genetic Supermarket: Law and Ethics of Selecting the Next Generation. New York: Routledge-Cavendish, 2007.
  • Roberts, Melina A. and David T. Wasserman, eds. Harming Future Persons: Ethics, Genetics and the Nonidentity Problem. New York: Springer, 2009.
  • Wilkinson, Stephen. Choosing Tomorrow’s Children: The Ethics of Selective Reproduction. New York: Oxford University Press, 2010.

Out of Print

  • Gordon, Jon W. The Science and Ethics of Engineering the Human Germ Line: Mendel's Maze. Hoboken, NJ: Wiley-Liss, 2003.
  • Haker, Hille and Deryck Veyleveld, eds. The Ethics of Genetics in Human Procreation. Burlington, VA: Ashgate, 2000.
  • McGee G. The Perfect Baby: Parenthood in the New World of Cloning and Genetics. Lanham, MD: Rowman & Littlefield, 2000.
  • Stock, Gregory, and John Campbell, eds. Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children. New York: Oxford University Press, 2000.

*** Designates Christian Resource

Updated October 2016

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