Improved Ophthalmic Care for Retinoblastoma Patients

描述(申请人提供)：这项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，并创新更有效和毒性更低的治疗方法。这些是：1.建立和验证蛋白质截断试验(PTT)以检测视网膜母细胞瘤胚系基因(RB1)突变，并确定突变分析是否可用于预测眼部疾病的表现。我们建议：a.发展PTT。B.进行聚焦DNA测序，以鉴定PTT检测到的RB1突变。C.确定突变分析是否可以用于预测眼部疾病的表现。ii.确定选定的新药理药物在Rb中的潜在临床应用。它们是：A.环孢素A，以及两种潜在的替代品，PSC-833和FK506。B.维甲酸，包括全反式维甲酸、ALRT1550、AM80、芬维甲酸、塔格列汀、9-顺式维甲酸和13-顺式维甲酸。c.烷化剂替莫唑胺。D.血脑屏障渗透剂RMP-7(Cereport)E.肿瘤特异性病毒制剂Onyx-015和Onyx-RB1，这些药物因其相对较低的毒性和潜在的治疗眼部肿瘤的疗效而被选择。这些药物在其他眼科疾病的治疗中也有潜在的实用价值。

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.