Antisense therapy for the treatment of visual loss in Usher syndrome

反义疗法治疗 Usher 综合征视力丧失

• 批准号: 10004041
• 负责人: Jennifer Jean Lentz
• 金额: $ 34.59万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004041
• 关键词: Affect; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Area; Auditory; Behavior; Blindness; Canada; Cells; Chemicals; Chemistry; Cilia; Clinic; Clinical; Clinical Research; Clinical Trials; Cochlea; Communication; Complex; Defect; Development; Disease; Dose; Drug Industry; Employment; Enrollment; Equilibrium; Eye diseases; Functional disorder; Future; Gene Proteins; Genes; Genetic; Genotype; Goals; Hair Cells; Health; Health education; Hearing; Human; Individual; Inherited; Intervention; Joints; Knock-in; Knock-in Mouse; Laboratories; Lead; Length; Life; Louisiana; Measurable; Measures; Medical; Messenger RNA; Modeling; Molecular; Mus; Mutation; National Institute on Deafness and Other Communication Disorders; Natural History; Nature; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Photoreceptors; Population; Protein Isoforms; Proteins; RNA; RNA Splicing; Rare Diseases; Research Support; Retina; Retinal Degeneration; Retinal Dystrophy; Route; Savings; Schedule; Structure; Synapses; Syndrome; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxicology; Transcript; Translations; Treatment Efficacy; USH1C gene; United States National Institutes of Health; Usher Proteins; Usher Syndrome; Usher Syndrome Type 1C; Variant; Vision; Visual; Visual impairment; Work; base; clinical center; clinical trial participant; cohort; deafness; drug candidate; effective therapy; first-in-human; gene replacement; gene replacement therapy; hearing impairment; improved; interest; mouse model; mutant; novel; preclinical efficacy; prospective; social; standard measure; standard of care; success; therapeutic candidate; therapy development; treatment strategy

Project Summary Individual rare diseases affect 6 – 8 % of the world population, which is limited compared to more common diseases. Thus, developing therapeutics for these conditions generates little interest from the pharmaceutical industry, resulting in a tremendous unmet medical need. However, development of therapies for rare diseases – especially in the context of underlying genetic and molecular mechanisms -- represents an area of great interest for the NIH. Usher syndrome is a rare disease characterized by concurrent hearing and vision loss. The loss of both hearing and vision creates a major communication burden and affects all aspects of life including health, education, social activities and employment. The long-term goals of this project are to develop an effective treatment for vision loss in Usher using antisense therapy; and establish the clinical parameters and measurable endpoints that could be used to determine the time to treatment and measure the potential therapeutic effect of testing antisense oligonucleotides (ASO) in future clinical trials. Usher syndrome is associated with mutations in sixteen genes creating four distinct clinical types. Usher-related genes and proteins express multiple tissue-specific variants that change over time, which creates a barrier to therapeutic strategies using gene-replacement therapy. To overcome this, we targeted the human 216A mutation in the USH1C gene that causes Type 1C Usher in the Acadian population, with an ASO that modulates mutant RNA splicing. Using a well validated Usher 1C mouse model that contains this human 216A mutation, we demonstrated that ASO treatment improves splicing of the Ush1c-RNA transcript and shows appreciable and significant rescue of vision and hearing. Therefore, the first aim of this study is to identify and characterize an USH1C-ASO drug therapy molecule that most effectively targets the 216A mutation and treats vision loss. We will test USH1C-targeted ASOs with different sequences and chemistries for efficacy and tolerability in Ush1c mice and patients’ cells. The second aim is to determine the most robust clinical endpoints and identify potential trial participants to guide a clinical trial. We have identified a cohort of 52 USH1C patients in the three participating clinical centers. The patients will be invited to enroll in a prospective natural history study where we will measure standard of care and novel retinal and visual parameters at 6-month intervals over a 2-year period. These tests will allow us to define the clinical parameters to determine the outcome of our future trial. Successful completion of the proposed studies, will identify a lead ASO-drug candidate, demonstrate its preclinical efficacy, determine measurable clinical outcomes to guide a first-in-man ASO-based treatment for vision loss in USH1C and identify a cohort of potential trial participants.

项目摘要 个别罕见疾病影响世界人口的6%-8%，与更常见的疾病相比，这是有限的。 疾病。因此，开发针对这些疾病的疗法几乎不会引起制药商的兴趣 工业，导致巨大的未得到满足的医疗需求。然而，罕见疾病的治疗方法的发展 -尤其是在潜在的遗传和分子机制的背景下--代表了一个伟大的领域 对美国国立卫生研究院感兴趣。Usher综合征是一种罕见的疾病，其特征是同时伴有听力和视力丧失。 听力和视力的丧失造成了重大的沟通负担，并影响到生活的方方面面 包括健康、教育、社会活动和就业。该项目的长期目标是开发 反义治疗对Usher失明的有效治疗；并建立临床参数 和可测量的终点，可用于确定治疗时间和测量潜力 未来临床试验中检测反义寡核苷酸的疗效。Usher综合征是 与16个基因的突变有关，形成了四种不同的临床类型。引座者相关基因和 蛋白质表达随着时间的推移而变化的多种组织特异性变异，这为治疗创造了障碍 使用基因替代疗法的策略。为了克服这一点，我们将人类216A突变定位于 在阿卡迪亚人群中导致1C型Usher的USH1C基因，带有调节突变RNA的ASO 拼接。使用一个经过良好验证的包含人类216A突变的Usher 1C小鼠模型，我们 证明ASO处理提高了Ush1c-RNA转录本的剪接，并显示出明显的 极大地挽救了视力和听力。因此，本研究的第一个目的是识别和表征一种 USH1C-ASO药物治疗分子，最有效地针对216A突变和治疗视力丧失。我们 将测试具有不同序列和化学成分的USH1C靶向ASO在Ush1c中的有效性和耐受性 老鼠和病人的细胞。第二个目标是确定最健壮的临床终点并确定 指导临床试验的潜在试验参与者。我们已经确定了三个病例中52名USH1C患者的队列 参与临床中心。患者将被邀请参加一项前瞻性的自然历史研究 我们将在两年内每隔6个月测量一次护理标准和新的视网膜和视力参数 句号。这些测试将使我们能够定义临床参数，以确定我们未来试验的结果。 成功完成拟议研究，将确定主要的ASO候选药物，证明其 临床前疗效，确定可测量的临床结果，以指导基于ASO的首例临床治疗 USH1C中的视力损失，并确定潜在试验参与者的队列。