Improved Ophthalmic Care for Retinoblastoma Patients

描述（由申请方提供）：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。我们建议通过改进的基因检测为遗传性眼部RB患者提供快速诊断和改善预后，并为这种眼科疾病创新更有效和毒性更小的治疗方法。这些建议是：建立并验证一种检测生殖系视网膜母细胞瘤基因（RB 1）突变的蛋白质截短试验（PTT），并确定突变分析是否可用于预测眼部疾病的表达。我们建议：A.开发PTT。B。进行聚焦DNA测序，以表征通过PTT检测到的RB 1突变。C.确定突变分析是否可用于预测眼部疾病的表达。确定所选新药物在RB中的潜在临床效用。它们是：A.环孢素A和两种潜在的替代品，PSC-833和FK 506。B。维甲酸类，包括全反式维甲酸、ALRT 1550、AM 80、芬维A胺、塔格列汀、9-顺式维甲酸和13-顺式维甲酸。烷化剂替莫唑胺。D.血脑屏障透化剂RMP-7（Cereport）。肿瘤特异性病毒制剂ONYX-015和ONYX-RB 1。选择这些制剂是因为它们相对低的毒性和在这种眼部肿瘤的管理中的潜在功效。这些药物在其他眼科疾病的管理中也具有潜在的实用性。

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.