Improved Ophthalmic Care for Retinoblastoma Patients

描述（由申请人提供）：本提案的长期目标是改善儿童眼部肿瘤视网膜母细胞瘤（RB）患者的眼科护理。我们建议通过改进基因检测，为遗传性眼RB患者提供快速诊断和改善预后，并创新更有效、毒性更小的眼病治疗方法。为了实现这些目标，提出了两个具体目标。这些是：1 .开发和验证用于检测生殖系视网膜母细胞瘤基因（RB1）突变的蛋白质截断试验（PTT），并确定突变分析是否可用于预测眼部疾病的表达。这一目标将分三个阶段实现。我们建议：A.发展PTT。B.进行重点DNA测序以表征PTT检测到的RB1突变。确定突变分析是否可用于预测眼部疾病的表达。确定选定的新药物在RB中的潜在临床应用价值。它们是：A.环孢素A，以及两种潜在的替代品PSC-833和FK506。B.类维甲酸，包括全反式维甲酸、ALRT1550、AM80、芬维甲酸、目标蛋白素、9-顺式维甲酸和13-顺式维甲酸。烷基化剂替莫唑胺。D.血脑屏障渗透剂RMP-7 （Cereport）。肿瘤特异性病毒制剂ONYX-015和ONYX-RB1。选择这些药物是因为它们的毒性相对较低，并且在治疗这种眼部肿瘤时具有潜在的疗效。这些药物在其他眼科疾病的治疗中也有潜在的效用。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to improve ophthalmic care for patients with a pediatric ocular tumor, retinoblastoma (RB). We propose to provide rapid diagnosis and improved prognosis for patients with heritable ocular RB through improved genetic testing, and to innovate more effective and less toxic therapies for this ophthalmic disease.In pursuit of these objectives, two specific aims are proposed. These are: I. To develop and validate a protein truncation test (PTT) for detection of germline retinoblastoma gene (RB1) mutations and to determine whether mutation analysis can be used to predict ocular disease expression.This aim will be accomplished in 3 stages. We propose to: A. Develop PTT. B. Perform focused DNA sequencing to characterize RB1 mutations detected by PTT. C. Determine whether mutation analysis can be used to predict ocular disease expression .II. To determine the potential clinical utility of selected new pharmacologic agents in RB. These are: A. Cyclosporin A, and two potential alternatives, PSC-833 and FK506. B. Retinoids, including all-trans retinoic acid, ALRT1550, AM80, fenretinide, Targretin, 9-cis retinoic acid, and 13-cis retinoic acid.C. The alkylating agent, temozolomide. D. The blood-brain barrier permeabilizer, RMP-7 (Cereport).E. The tumor-specific viral agents, ONYX-015 and ONYX-RB1.These agents are chosen for their relatively low toxicity and potential efficacy in the management of this ocular tumor. These agents also have potential utility in the management of other ophthalmic disorders.