Rapid Upregulation of Interferon-Regulated and Chemokine mRNAs upon Injection of 108 International Units, but Not Lower Doses, of Adenoviral Vectors into the Brain

doi:10.1128/JVI.00166-06

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Rapid Upregulation of Interferon-Regulated and Chemokine mRNAs upon Injection of 10⁸ International Units, but Not Lower Doses, of Adenoviral Vectors into the Brain

Jeffrey M. Zirger,¹ Carlos Barcia,¹ Chunyan Liu,¹ Mariana Puntel,¹ Ngan Mitchell,² Iain Campbell,²^,3 Maria Castro,¹ and Pedro R. Lowenstein¹^*

Board of Governors’ Gene Therapeutics Research Institute, Cedar-Sinai Medical Center, and Departments of Medical and Molecular Pharmacology and Medicine, David Geffen School of Medicine, University of California, Los Angeles, California,¹ Scripps Research Institute, La Jolla, California,² University of Sydney, Sydney, Australia³

Received 24 January 2006/ Accepted 6 March 2006

The innate immune response, characterized by the rapid inductionof proinflammatory genes, plays an important role in immuneresponses to viral vectors utilized in gene therapy. We demonstratethat several innate proinflammatory mRNAs, i.e., those codingfor the interferon (IFN)-regulated proteins interferon regulatoryfactor 1, 2',5'-oligoadenylate synthetase, and double-stranded-RNA-dependentprotein kinase as well as those coding for the chemokines RANTES,IFN- ${gamma}$ -inducible protein 10, and monocyte chemoattractant protein1, were all increased in a statistically significant mannerin response to 1 x 10⁸ IU, but not lower doses, of a first-generationadenovirus injected into the naïve brain. This indicatesthe presence of a threshold dosage of adenovirus needed to elicitan acute innate inflammatory response.

* Corresponding author. Mailing address: Gene Therapeutics Research Institute, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 423-7330. Fax: (310) 423-7308. E-mail: lowensteinp{at}cshs.org.

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