Translational Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa

视紫红质常染色体显性遗传性色素性视网膜炎的转化基因治疗

• 批准号: 8634788
• 负责人: William A. Beltran
• 金额: $ 134.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634788
• 关键词: Accounting; Alleles; Animal Model; Animals; Applications Grants; Basic Science; Biodistribution; Biological Preservation; Canis familiaris; Catalytic RNA; Ciliary Neurotrophic Factor; Clinical Treatment; Clinical Trials; Collaborations; Complementary DNA; Coupled; Data; Development; Disease; Dominant-Negative Mutation; Future; Gene Mutation; Genes; Goals; Heterogeneity; Human; Immune Tolerance; Immune response; Instruction; Lead; Mediating; Messenger RNA; Modeling; Morphology; Mus; Mutation; Natural History; Outcome; Outcome Measure; Patient Participation; Patients; Phase; Phase I Clinical Trials; RPE65 protein; Reagent; Research; Research Infrastructure; Research Personnel; Resistance; Resources; Retina; Retinal; Retinitis Pigmentosa; Rhodopsin; Safety; Scientist; Small Interfering RNA; Staging; Structure; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicology; Translating; Translations; Treatment Efficacy; Viral; Viral Vector; Vision; Work; achromatopsia; adeno-associated viral vector; base; clinically relevant; comparative efficacy; experience; gain of function; gene therapy; gene therapy clinical trial; human disease; inherited retinal degeneration; interdisciplinary approach; man; member; mouse model; mutant; patient population; pre-clinical; promoter; reagent testing; research study; retinal rods; safety study; safety testing; success; translational study; treatment strategy; vector

DESCRIPTION (provided by applicant): A multi-investigator, multi-center research plan is proposed to develop and test gene-based retinal therapy in animal models (mouse and dog) for translation to patients with autosomal dominant RP caused by mutations in the rhodopsin gene (RHO). RHO mutations constitute one of the most common molecularly-identified causes of human RP, and more than 100 of them account for > 12 % of RP. The proposal has been divided into 4 aims that will: (Aim#1) develop viral vectors, promoters, knockdown constructs and replacement cDNAs, and compare the efficacy of a RHO cDNA augmentation approach, to that of an allele-independent knockdown and replacement strategy in two mouse models; (Aim #2) evaluate in a large animal model (dog) which of these strategies provides optimal rescue of rods, (Aim #3) develop outcome measures for clinical trials of gene therapy in RHO-ADRP patients, and (Aim #4) evaluate the optimal strategy and vector construct (based on results of Aims #1 and 2) in pre-clinical safety studies. Six coordinated modules (M) are described, each with a specific set of aims that contributes in a unique but complementary way to the translational studies. M1 (Vector Development) will provide AAVs carrying knockdown (siRNA, ribozymes) reagents, and resistant (hardened) RHO cDNAs. M2 (Small Animal-mouse- Therapy Studies) will test the 2 gene therapy approaches in two mouse models. M3 (Large Animal Experiemntal Support) will produce the dogs, and provide infrastructure resources for this work). M4 (Large anima I- dog - Therapy Studies) will test the 2 approaches in a naturally -occurring canine model of RHO-ADRP. M5 (Human RHO-ADRP) will identify retinal regions that can be targeted for focal retinal therapy in patients. M6 (Vector safety studies in Animals) will conduct GLP-based preclinical toxicology and biodistribution studies in small and large animals to test the safety of the optimal ("lead") therapeutic vector as the essential first step ro FDA consideration of an IND for a future Phase I Clinical Trial. The research studies described in this proposal represent a continuation of a longstanding collaboration between the module scientists that already has brought retinal gene therapy for RPE65-LCA patients to a Phase I clinical trial.

描述（由申请人提供）：提出了一种多企业，多中心研究计划，以开发和测试基于基因的动物模型（小鼠和狗）基于基因的视网膜治疗，以转化为由杜鹃花基因突变（Rho）突变引起的常染色体显性RP患者。 RHO突变构成了人RP最常见的分子原因之一，其中100多个占RP的12％。该提案已分为4个目标：（目标＃1）开发病毒矢量，启动子，敲低构建体和替换CDNA，并比较了Rho cdna增强方法的功效，并在两种小鼠模型中与等位基因独立的敲低和替换策略的效力； （AIM＃2）在大型动物模型（DOG）中评估这些策略中的最佳挽救杆，（AIM＃3）在Rho-ADRP患者中制定了基因治疗临床试验的结果指标，并且（AIM＃4）评估最佳策略和矢量构建体（基于AIM＃1和2）在临床前安全研究中。描述了六个协调模块（M），每个模块都具有一组特定的目标，这些目标以独特但互补的方式促进转化研究。 M1（载体开发）将提供携带敲低的AAV（siRNA，核酶）试剂和耐药性（硬化）RHO CDNA。 M2（小型动物大鼠治疗研究）将在两种小鼠模型中测试两种基因治疗方法。 M3（大型动物经验支持）将产生狗，并为这项工作提供基础设施资源）。 M4（大型Anima I-狗 - 治疗研究）将在Rho -Adrp的自然犬类模型中测试两种方法。 M5（人类Rho-ADRP）将确定可以针对患者局灶性视网膜治疗的视网膜区域。 M6（动物的载体安全研究）将对小动物和大型动物进行基于GLP的临床前毒理学和生物分布研究，以测试最佳（“铅”）治疗载体的安全性，这是对未来I期I临床试验的IND的重要第一步。该提案中描述的研究代表了模块科学家之间长期合作的延续，该模块科学家已经将视网膜基因疗法用于RPE65-LCA患者参加了I期临床试验。