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AAV-mediated Local Delivery of Interferon-β for the Treatment of Retinoblastoma in Preclinical Models

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Abstract

Interferon-β (IFN-β) has been found to have anti-tumor properties against a variety of malignancies through different mechanisms. However, clinical trials involving systemic administration of IFN-β have been hampered by secondary toxicity and the short half-life of IFN-β in the circulation. In order to circumvent these limitations, we have developed an adeno-associated viral (AAV) vector gene-therapy approach to deliver IFN-β to tumors. In this study, we tested the efficacy of AAV-mediated local delivery of IFN-β for the treatment of retinoblastoma in preclinical models. Retinoblastoma is an ideal candidate for gene-therapy-based anti-cancer treatment because target cell transduction and, therefore, IFN-β delivery can be contained within the ocular environment, thereby minimizing systemic toxicity. We report here that retinoblastoma cell lines exhibit pleiotropic responses to IFN-β consistent with previous studies on a variety of tumor cell lines. Intravitreal injection of AAV-IFN-β resulted in efficient retinal infection and sustained IFN-β production in the eye with minimal systemic exposure. Vector spread outside of the eye was not detected. Using our orthotopic xenograft model of retinoblastoma, we found that intravitreal injection of AAV-IFN-β had a potent anti-tumor effect in vivo. These data suggest that AAV-mediated delivery of IFN-β may provide a complementary approach to systemic chemotherapy which is the standard of care for retinoblastoma around the world.

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Acknowledgments

We thank Dr. John Gray and the staff of the Vector Core Facility at St. Jude Children’s Research Hospital for their assistance with pseudotyped AAV. This study was supported by the Alliance for Cancer Gene Therapy (AMD), Grant No. T32-CA070089 from the National Cancer Institute, Grants (to M.A.D.) from the National Institutes of Health (EY04867), Cancer Center Support from the National Cancer Institute (CA21766), the American Cancer Society Research to Prevent Blindness (RSG-06-03-01), and by the American Lebanese Syrian Associated Charities. M.A.D. is a Pew Scholar.

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Authors and Affiliations

  1. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Chie-Schin Shih, Nikia Laurie, Jeremy Holzmacher & Michael A. Dyer

  2. Department of Pediatric Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Chie-Schin Shih

  3. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Yunyu Spence & Andrew M. Davidoff

  4. Department of Hematology, University College London, London, UK

    Amit C. Nathwani

  5. Department of Surgery, University of Tennessee Health Sciences Center, Memphis, TN, 38105, USA

    Andrew M. Davidoff

  6. Department of Ophthalmology, University of Tennessee Health Sciences Center, Memphis, TN, 38105, USA

    Michael A. Dyer

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  1. Chie-Schin Shih
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  2. Nikia Laurie
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Correspondence to Michael A. Dyer.

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Shih, CS., Laurie, N., Holzmacher, J. et al. AAV-mediated Local Delivery of Interferon-β for the Treatment of Retinoblastoma in Preclinical Models. Neuromol Med 11, 43–52 (2009). https://doi.org/10.1007/s12017-009-8059-0

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