Shih Chie-Schin, Laurie Nikia, Holzmacher Jeremy, Spence Yunyu, Nathwani Amit C, Davidoff Andrew M, Dyer Michael A
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Neuromolecular Med. 2009;11(1):43-52. doi: 10.1007/s12017-009-8059-0. Epub 2009 Mar 22.
Interferon-beta (IFN-beta) has been found to have anti-tumor properties against a variety of malignancies through different mechanisms. However, clinical trials involving systemic administration of IFN-beta have been hampered by secondary toxicity and the short half-life of IFN-beta in the circulation. In order to circumvent these limitations, we have developed an adeno-associated viral (AAV) vector gene-therapy approach to deliver IFN-beta to tumors. In this study, we tested the efficacy of AAV-mediated local delivery of IFN-beta 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-beta delivery can be contained within the ocular environment, thereby minimizing systemic toxicity. We report here that retinoblastoma cell lines exhibit pleiotropic responses to IFN-beta consistent with previous studies on a variety of tumor cell lines. Intravitreal injection of AAV-IFN-beta resulted in efficient retinal infection and sustained IFN-beta 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-beta had a potent anti-tumor effect in vivo. These data suggest that AAV-mediated delivery of IFN-beta may provide a complementary approach to systemic chemotherapy which is the standard of care for retinoblastoma around the world.
干扰素-β（IFN-β）已被发现可通过不同机制对多种恶性肿瘤具有抗肿瘤特性。然而，涉及全身给药IFN-β的临床试验受到继发毒性和IFN-β在循环中半衰期短的阻碍。为了规避这些限制，我们开发了一种腺相关病毒（AAV）载体基因治疗方法，将IFN-β递送至肿瘤。在本研究中，我们在临床前模型中测试了AAV介导的局部递送IFN-β治疗视网膜母细胞瘤的疗效。视网膜母细胞瘤是基于基因治疗的抗癌治疗的理想候选者，因为靶细胞转导以及因此的IFN-β递送可以局限于眼内环境，从而将全身毒性降至最低。我们在此报告，视网膜母细胞瘤细胞系对IFN-β表现出多效性反应，这与先前对多种肿瘤细胞系的研究一致。玻璃体内注射AAV-IFN-β导致视网膜有效感染并在眼中持续产生IFN-β，全身暴露最小。未检测到载体在眼外扩散。使用我们的视网膜母细胞瘤原位异种移植模型，我们发现玻璃体内注射AAV-IFN-β在体内具有强大的抗肿瘤作用。这些数据表明，AAV介导的IFN-β递送可能为全身化疗提供一种补充方法，全身化疗是世界各地视网膜母细胞瘤的标准治疗方法。
