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Formulation Considerations for DNA-Based Therapeutics

  • Chapter
Cellular Drug Delivery

Abstract

The ability to deliver genes to cells and tissues in vivo offers the potential to develop potent vaccines and treat many hereditary diseases that are currently considered incurable, e.g., cancer, cystic fibrosis (CF), severe combined immunodeficiency (SCID), and acquired immune deficiency syndrome (AIDS) (1-6). Considering the tremendous promise of DNA-delivery technology, in addition to the extensive genetic information now available from the Human Genome Project, it is not surprising that gene therapy is being touted as the next revolution in medicine. Although a strict definition of “gene therapy” would be limited to therapeutic approaches that aim to use polynucleotides as a template for the in vivo production of proteins, the term is often used to refer to a wide variety of strategies that employ nucleotide-based molecules (e.g., vaccines, antisense, ribozymes, siRNA). To date, 70 clinical protocols have been approved for the delivery of naked DNA, comprising approx 11% of the total number of gene-therapy clinical protocols (http://www.wiley.co.uk/genetherapy/clinical). Slightly more studies (~12%) have employed nonviral, lipid-based vectors to facilitate DNA delivery. In comparison, the large majority of clinical gene therapy trials (>70%) utilizes viruses to deliver therapeutic genes because viruses are more efficient than contemporary synthetic gene-delivery systems. The higher efficiency of viruses should not be surprising if we recognize that these organisms have been evolving their gene-delivery machinery for billions of years. In contrast, the development of nonviral systems for therapeutic gene delivery can be traced back a mere 15 years (7). Although more efficient nonviral gene-delivery systems continue to be developed, synthetic systems have yet to replicate the efficiency of viruses. One significant drawback of viral delivery is the immunogenicity of viruses, which causes significant inflammation in vivo (8), and eliminates the potential for multiple dosing (anyone who has ever had a cold is familiar with the fever and inflammation associated with an immune response to viruses). In fact, the adverse reactions associated with viral delivery have been implicated as the cause of death in clinical trials (9,10). Also, a clinical trial involving liver infusion of an adenoassociated virus (AAV) for the treatment of hemophilia B was halted because of the presence of the viral vector in patient semen, and the concern that the genetic alteration could be passed to offspring (11). More recently, two patients treated with ex vivo genetherapy for the treatment of SCID have developed leukemia owing to insertional mutagenesis caused by the retroviral vector used in the study (12,13). Considering the potential safety risk involved in employing viruses as a therapeutic moiety, there is renewed interest in developing safe, efficient, nonviral gene-delivery systems.

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Authors
  1. Thomas J. Anchordoquy
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  2. Taylor K. Armstrong
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  3. Marion d. C. Molina
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  4. S. Dean Allison
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  5. Ye Zhang
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  6. Mayank M. Patel
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  7. Yvonne K. Lentz
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  8. Gary S. Koe
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Editors and Affiliations

  1. School of Pharmacy, Temple University, Philadelphia, PA, USA

    D. Robert Lu PhD

  2. College of Pharmacy, University of Georgia, Athens, GA, USA

    Svein Øie PhD

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Anchordoquy, T.J. et al. (2004). Formulation Considerations for DNA-Based Therapeutics. In: Lu, D.R., Øie, S. (eds) Cellular Drug Delivery. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-745-1_13

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  • DOI: https://doi.org/10.1007/978-1-59259-745-1_13

  • Publisher Name: Humana Press, Totowa, NJ

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