Antisense therapy for the treatment of visual loss in Usher syndrome

项目摘要 个别罕见病影响6 - 8%的世界人口，这是有限的相比，更常见的 疾病因此，开发用于这些病症的治疗剂几乎没有引起制药商的兴趣。 行业，导致巨大的未满足的医疗需求。然而，罕见疾病的治疗方法的发展 - 特别是在潜在的遗传和分子机制的背景下--代表了一个非常重要的领域， 对NIH的兴趣。Usher综合征是一种罕见的疾病，其特征是同时出现听力和视力丧失。 听力和视力的丧失造成了重大的沟通负担，影响到生活的各个方面 包括保健、教育、社会活动和就业。该项目的长期目标是开发 使用反义疗法有效治疗Usher视力丧失;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在的 在未来的临床试验中测试反义寡核苷酸（阿索）的治疗效果。Usher综合征 与16个基因的突变相关，产生了4种不同的临床类型。Usher相关基因和 蛋白质表达多种组织特异性变体，这些变体随着时间的推移而变化，这对治疗性免疫缺陷形成了障碍。 使用基因替代疗法。为了克服这一点，我们针对人类216 A突变， USH 1C基因导致埃塞俄比亚人群中的1C型Usher，具有调节突变RNA的阿索 拼接使用一个经过充分验证的Usher 1C小鼠模型，该模型含有人类216 A突变，我们 证明阿索处理改善了Ush 1c-RNA转录物的剪接，并显示出明显的 对视力和听力的重大拯救。因此，本研究的第一个目的是识别和表征一种 USH 1C-ASO药物治疗分子，最有效地靶向216 A突变并治疗视力丧失。我们 将在Ush 1c中测试具有不同序列和化学的USH 1C靶向ASO的疗效和耐受性 老鼠和病人的细胞。第二个目标是确定最可靠的临床终点， 潜在的试验参与者指导临床试验。我们已经确定了一个队列的52 USH 1C患者在三个 参与的临床中心。患者将被邀请参加一项前瞻性自然史研究， 我们将在2年内每隔6个月测量一次标准治疗和新的视网膜和视力参数。 期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。 成功完成拟定的研究，将确定一种主要的ASO候选药物，证明其 临床前疗效，确定可测量的临床结局，以指导首次基于人体的ASO治疗， USH 1C的视力丧失，并确定一组潜在的试验参与者。

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.