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

Pron病是一种致命的、无法治愈的神经退行性疾病，每6000人中就有1人死亡，通常会导致迅速进展的痴呆症，并在首次症状不到半年内死亡。包括CreutzFeldt-Jakob病、致死性家族性失眠和Gerstmann-Straussler-Scheinker病在内的各种亚型的Prion病都由一个单一的分子机制统一起来：脑中PrP的错误折叠。PrP由PrNP基因编码，天然形式不致病，存在于所有哺乳动物的大脑中。但它能够发生构象变化，转变为PrP蛋白，通过破坏其他PrP分子进行传播，最终导致神经元损伤和死亡。几十年的研究支持降低大脑中的PrP作为预防或推迟PrP疾病的发病和减缓进展的治疗策略，而PrP似乎对健康生活是必不可少的。然而，寻找一种具有足够的脑分布、效力、耐受性和耐受性的治疗方法来在这种无情的进行性全脑疾病中实现对PrP的充分抑制是一个主要的挑战。二价siRNA(di-siRNA)技术于2019年首次被描述，是一种新型的化学修饰的寡核苷酸治疗方法，可以广泛、深入、持久地抑制大脑中的靶RNA分子。在这里，我们建议开发一种针对人PRNP RNA的di-siRNA先导化合物，作为Pron疾病的治疗药物。在这个项目中，我们将实施生产流程，规模化生产，并对我们的先导di-siRNA进行质量测试，验证化合物的动物和人体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。该项目的成功将产生一种候选药物，具有改变人类Pron疾病治疗的潜力。

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.