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Gene Therapy for Mucositis

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Genomics, Personalized Medicine and Oral Disease

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Abstract

A major dose limiting toxicity of chemoradiotherapy of head and neck cancer is mucositis. Attempts to decrease radiation damage have included both locally delivered and systemic strategies. A highly effective locally applied radioprotectant is Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL), which has been shown in animal models with fractionated radiotherapy to the head and neck to be an effective radioprotector, when delivered between each radiotherapy fraction. Intraoral administration of Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL) prior to single fraction irradiation or immediately before each of multiple fractions of head and neck irradiation significantly reduces oral cavity and oropharyngeal mucositis in the C57BL/6NHsd model. The mechanism is dependent upon mitochondrial targeting of the MnSOD transgene product. A phase I Clinical Trial of administration of MnSOD-PL to patients twice a week during chemoradiotherapy of lung cancer has demonstrated significant protection of the esophagus in patients, who swallow MnSOD-PL. A “mouthwash” administration of MnSOD-PL is being tested in a clinical trial at the University of Pittsburgh Cancer Institute. Reduction of irradiation-induced oral cavity and oropharyngeal mucositis should allow dose escalation in clinical trials of chemoradiotherapy and biological response modifier therapy of head and neck cancers, but more importantly, reduce significant side effects of treatment. An attractive evolution of this gene therapy approach has been the development of small molecule radioprotectants, prominently mitochondrial targeted 4-amino tempo. Mitochondrial targeting has been optimized with the development of hemigramicidin linkers, which deliver concentrated drug to the mitochondria thereby limiting radiation-induced apoptosis. The GS-nitroxide, JP4-039, then delivered in a novel F15 tissue targeted emulsion provides significant radioprotection of normal oral cavity and oropharyngeal mucosa when delivered before single fraction or between fractions of radiotherapy. The ease of administration of oral cavity/oropharynx radioprotectants makes their application in clinical translational protocols both safe and feasible.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Pittsburgh Medical Center, 5150 Centre Avenue, Rm. 533, 15232, Pittsburgh, PA, USA

    Prof. Joel S. Greenberger MD, FACRO, FACR & Michael W. Epperly PhD

  2. Department of Chemistry and Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA, USA

    Peter Wipf PhD

  3. Department of Pharmaceutical Science, University of Pittsburgh, Pittsburgh, PA, USA

    Song Li PhD & Xiang Gao PhD

  4. Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Valerian Kagan PhD

Authors
  1. Prof. Joel S. Greenberger MD, FACRO, FACR
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  2. Michael W. Epperly PhD
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  3. Peter Wipf PhD
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  4. Song Li PhD
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  5. Valerian Kagan PhD
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  6. Xiang Gao PhD
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Corresponding author

Correspondence to Joel S. Greenberger MD, FACRO, FACR .

Editor information

Editors and Affiliations

  1. Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Stephen T. Sonis, DMD, DMSc

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© 2015 Springer International Publishing Switzerland

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Greenberger, J., Epperly, M., Wipf, P., Li, S., Kagan, V., Gao, X. (2015). Gene Therapy for Mucositis. In: Sonis, DMD, DMSc, S. (eds) Genomics, Personalized Medicine and Oral Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-17942-1_16

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