Advancement of Prion Protein-Lowering Divalent siRNA Therapy for Prion Disease

朊病毒蛋白降低二价 siRNA 治疗朊病毒病的进展

• 批准号: 10721465
• 负责人: Eric Vallabh Minikel
• 金额: $ 80.05万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721465
• 关键词: Animal Model; Animals; Antisense Oligonucleotides; Awareness; Biodistribution; Biological Assay; Biological Markers; Brain; Brain Diseases; Brain region; Central Nervous System; Cerebral hemisphere; Cerebrospinal Fluid; Cessation of life; Chemicals; Chronic; Clinical; Clinical Research; Creutzfeldt-Jakob Syndrome; Data; Dementia; Development; Disease; Dose; Dose Limiting; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Event; Fatal Familial Insomnia; Funding; Future; Genes; Genetic; Gerstmann-Straussler-Scheinker Disease; Goals; Grant; Human; Human Cell Line; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Life; Macaca fascicularis; Mammals; Manufacturer; Modality; Molecular; Molecular Conformation; Mus; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurons; Oligonucleotides; Onset of illness; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Pilot Projects; PrP; PrP gene; Preventive measure; Prion Diseases; Prions; Process; Production; Proteins; Qualifying; RNA; Rattus; Reporting; Research Personnel; Research Support; Residual state; Risk; Small Interfering RNA; Symptoms; Technology; Testing; Therapeutic; Time; Toxic effect; United States Food and Drug Administration; Validation; Work; clinical development; conditioning; drug candidate; drug production; effective therapy; first-in-human; genetic predictors; genetic testing; human study; humanized mouse; knock-down; manufacturing process; medical schools; meetings; novel; pre-clinical; prevent; protein expression; protein misfolding; response; standard of care; success; therapeutic siRNA; transcriptome sequencing

Prion disease is a uniformly fatal, incurable neurodegenerative disease that causes 1 in every 6,000 deaths and typically leads to rapidly progressive dementia and death within less than half a year of first symptom. The various subtypes of prion disease including Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker disease are all unified by a single molecular mechanism: misfolding of the prion protein (PrP) in the brain. PrP, encoded by the gene PRNP, is not pathogenic in its native form and is present in the brains of all mammals. But it is capable of undergoing a conformational change into a prion which spreads by corrupting other PrP molecules, eventually causing neuronal damage and death. Decades worth of research supports lowering PrP in the brain as a therapeutic strategy to prevent or delay onset, and slow the progression, of prion disease, and PrP appears to be dispensable for healthy life. However, finding a therapeutic modality with sufficient brain distribution, potency, durability, and tolerability to achieve adequate suppression of PrP in this relentlessly progressive whole brain disease is a major challenge. Divalent siRNA (di-siRNA) technology, first described in 2019, is a new class of chemically modified oligonucleotide therapeutic that can provide broad, deep, persistent suppression of target RNA molecules in the brain. Here we propose to develop a di-siRNA lead compound against the human PRNP RNA as a therapeutic for prion disease. In this project we will implement a manufacturing process, scale production, and perform quality testing of our lead di-siRNA, validate bioanalytical assays needed for animal and human studies of the compound, perform pharmacology and toxicology studies needed to support clinical development of a drug, and engage with the U.S. Food and Drug Administration to establish a development path for di-siRNA. Success in this project will yield a drug candidate with the potential to transform therapy of human prion disease.

朊病毒病是一种致命的、不可治愈的神经退行性疾病，每6,000例死亡中就有1例，通常在首次出现症状后不到半年内导致快速进展性痴呆和死亡。朊病毒病的各种亚型，包括克雅氏病，致命的家族性失眠症和Gerstmann-Straussler-Scheinker病，都是由一个单一的分子机制统一的：朊病毒蛋白（PrP）在大脑中的错误折叠。PrP由PRNP基因编码，其天然形式不具有致病性，并且存在于所有哺乳动物的大脑中。但它能够经历构象变化成为朊病毒，朊病毒通过破坏其他PrP分子而传播，最终导致神经元损伤和死亡。数十年的研究支持降低大脑中的PrP作为预防或延迟朊病毒疾病发作并减缓其进展的治疗策略，PrP似乎对健康生活至关重要。然而，找到一种具有足够的脑分布、效力、耐久性和耐受性的治疗方式，以在这种无情的进行性全脑疾病中实现对PrP的充分抑制是一个重大挑战。二价siRNA（di-siRNA）技术于2019年首次描述，是一类新型化学修饰的寡核苷酸治疗剂，可以对大脑中的靶RNA分子进行广泛、深入、持久的抑制。在这里，我们建议开发一种针对人PRNP RNA的双siRNA先导化合物作为朊病毒疾病的治疗剂。在这个项目中，我们将实施一个制造过程，规模生产，并进行质量测试，我们的铅di-siRNA，验证所需的动物和人体研究的化合物的生物分析测定，进行药理学和毒理学研究所需的支持药物的临床开发，并与美国食品和药物管理局合作，建立一个发展道路di-siRNA。该项目的成功将产生一种有潜力改变人类朊病毒疾病治疗的候选药物。