Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs

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  • Pleticha, Josef
    • Other Affiliation: Departments of Anesthesiology, Oncology, and the Cancer Center, Mayo Clinic, Rochester, MN, USA
  • Heilmann, Lukas F
    • Other Affiliation: Departments of Anesthesiology, Oncology, and the Cancer Center, Mayo Clinic, Rochester, MN, USA
  • Evans, Christopher H
    • Other Affiliation: Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN, USA
  • Asokan, Aravind
    • Affiliation: School of Medicine, Gene Therapy Center
  • Samulski, R. Jude
    • Affiliation: School of Medicine, Gene Therapy Center
  • Beutler, Andreas S
    • Other Affiliation: Departments of Anesthesiology, Oncology, and the Cancer Center, Mayo Clinic, Rochester, MN, USA
Abstract
  • Abstract Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.
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Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Josef Pleticha et al.; licensee BioMed Central Ltd.
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Journal title
  • Molecular Pain
Journal volume
  • 10
Journal issue
  • 1
Page start
  • 54
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1744-8069
Bibliographic citation
  • Molecular Pain. 2014 Sep 02;10(1):54
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 26, 2015

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