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

朊病毒病是一种致命的、无法治愈的神经退行性疾病，每6000例死亡中就有1例死亡，通常会在首次出现症状后不到半年的时间内导致迅速进展性痴呆和死亡。包括克雅氏病、致死性家族性失眠症和Gerstmann-Straussler-Scheinker病在内的朊病毒疾病的各种亚型都由一个单一的分子机制统一：大脑中朊病毒蛋白（PrP）的错误折叠。PrP由基因PRNP编码，其原生形式不具有致病性，存在于所有哺乳动物的大脑中。但它能够经历构象变化，变成朊病毒，通过腐蚀其他PrP分子传播，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作为预防或延缓朊病毒疾病发病和减缓进展的治疗策略，PrP似乎对健康生活是不可或缺的。然而，在这种不断进展的全脑疾病中，寻找一种具有足够的脑分布、效力、持久性和耐受性的治疗方式来实现充分抑制PrP是一项重大挑战。二价siRNA （di-siRNA）技术于2019年首次被描述，是一类新的化学修饰的寡核苷酸治疗方法，可以对大脑中的靶RNA分子进行广泛、深度、持续的抑制。在这里，我们建议开发一种针对人类PRNP RNA的双sirna先导化合物作为治疗朊病毒疾病的药物。在这个项目中，我们将实施一个制造过程，规模生产，并对我们的先导di-siRNA进行质量测试，验证该化合物的动物和人类研究所需的生物分析分析，进行支持药物临床开发所需的药理学和毒理学研究，并与美国食品和药物管理局合作建立di-siRNA的开发路径。这个项目的成功将产生一种候选药物，有可能改变人类朊病毒疾病的治疗方法。

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.