Preclinic dose and delivery regime optimization and long-term efficacy evaluation of ribitol treatment for FKRP related dystroglycanopathy

核糖醇治疗 FKRP 相关肌营养不良症的临床前剂量和给药方案优化及长期疗效评估

• 批准号: 9810301
• 负责人: Qi L Lu
• 金额: $ 37.83万
• 依托单位: CAROLINAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810301
• 关键词: Animal Model; Antibodies; Binding; Biochemical; Cells; Cessation of life; Characteristics; Clinic; Defect; Development; Disease; Dose; Drug Kinetics; Fibrosis; Genes; Goals; Heterozygote; Homozygote; Impairment; Investigational Therapies; Laboratories; Laminin; Lead; Measures; Mediating; Membrane; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Muscular Dystrophies; Mutant Strains Mice; Mutation; Myocardium; Nature; Pathology; Pathway interactions; Patients; Phase; Phenotype; Polysaccharides; Principal Investigator; Qi; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Route; Safety; Severities; Skeletal Muscle; Structure; Testing; Therapeutic; TimeLine; Toxic effect; Transferase; Transgenes; Treatment Efficacy; Variant; Water; Western Blotting; Xylitol; biglycan; clinical application; clinically relevant; cohort; disease phenotype; dosage; drinking water; dystroglycanopathy; efficacy evaluation; fukutin related protein; gene therapy; glycosylation; heart function; inorganic phosphate; loss of function; mouse model; mutant; mutant mouse model; novel; pre-clinical; programs; side effect

Program Director/Principal Investigator (Last, First, Middle): Lu Qi Long Project Summary Mutations in FKRP gene cause muscular dystrophy with wide variation in severity with characteristic biochemical feature of defect in glycosylation of -DG. The progressive nature of the disease leads to a continuous loss of muscle fibers and increase in fibrosis, and finally loss of muscle function and ultimately failure of respiratory and cardiac functions, leading to early death. Currently no treatment is available although several experimental therapies are being tested in animal models. Recently, FKRP has been identified as a ribitol-5-phosphate transferase using CDP-ribitol as the substrate for the extension of the laminin binding biglycan (matriglycan) on -DG, a critical step for muscle integrity. Earlier study suggests that ribitol supplement can lead to an increase of CDP-ribitol levels in cells. We also demonstrated recently that mutant FKRPs retain sufficient levels of function to glycosylate -DG by AAV mediated gene therapy with mutant P448L FKRP as the transgene. We have now demonstrated that supplement of ribitol increases levels of matriglycan in our clinically relevant P448L mutant mouse model, resulting in significant improvement in muscle pathology and functions in both cardiac and skeletal muscles. This opens a novel, highly specific and clinically applicable means to treat the majority of FKRP muscular dystrophy. In this proposal, we will first optimize dosage and administration regime of ribitol in fkrp P448L mutant mouse model by testing a range of doses with both routes of gavage administration and in drinking water. The effects will be evaluated by levels of functional glycosylation and improvement of dystrophic pathology. We will then examine long-term efficacy (12 months) and safety of the selected dosing and delivery regime of ribitol in three strains of FKRP mutant mice, P448L, L276I homozygote, and P448L/L276I compound heterozygotes bearing clinically relevant mutations in more than 90% patients and representing diseases from mild to severe dystrophic phenotypes. These mutant strains have been established in the McColl Lockwood Laboratory. The aim is to establish at least one dose and delivery regime with long-term efficacy for further development towards clinic trials. The goal of this proposal is to establish a practically deliverable dosing and treatment regime with long- term therapeutic efficacy in clinically relevant mouse models for IND application. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目总监/首席研究员（最后，第一个，中间）：lu Qi Long 项目摘要 FKRP基因的突变引起肌肉营养不良，严重程度差异很大 -DG糖基化缺陷的生化特征。该疾病的渐进性导致 肌肉纤维的连续损失和纤维化的增加，最后损失肌肉功能，最终 呼吸道和心脏功能的失败，导致早期死亡。目前没有治疗 尽管在动物模型中测试了几种实验疗法。 最近，FKRP已被鉴定为使用CDP-核醇作为Ribitol-5-磷酸转移酶 延伸层粘连蛋白结合大型群（Matriglycan）的底物，这是肌肉的关键步骤 正直。较早的研究表明，核能补充剂可以导致细胞中CDP核醇水平的升高。我们 最近还证明了突变体FKRP保留了足够水平的功能来通过AAV糖基酸-DG 用突变体P448L FKRP作为转化的介导的基因治疗。我们现在已经证明了 补充核能在我们临床相关的p448l突变小鼠模型中增加了基质的水平， 导致心脏和骨骼肌的肌肉病理学和功能显着改善。 这打开了一种新颖的，高度特异性和临床适用的方法，用于治疗大多数FKRP肌肉 营养不良。 在此提案中，我们将首先优化FKRP P448L突变体中核糖醇的剂量和给药状态 小鼠模型通过测试两种剂量的剂量，并在饮用水中进行防护途径和饮用水。这 效应将通过功能性糖基化水平和营养不良病理学的改善来评估。我们将 然后检查长期有效性（12个月）以及选定的剂量和递送条件的安全性 FKRP突变小鼠的三种菌株，P448L，L276I纯合子和P448L/L276I化合物 在90％以上的患者中，具有临床相关突变的杂合子，代表疾病 从轻度到重度营养不良的表型。这些突变菌株已在McColl中建立 洛克伍德实验室。目的是至少建立一种具有长期效率的剂量和分娩制度 进一步发展临床试验。 该提案的目的是建立一种长期可交付的剂量和治疗方案 用于IND应用的临床相关小鼠模型中的术语治疗有效性。 PHS 398/2590（修订版06/09）页面延续格式页面