Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimer’s disease, Parkinson’s disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are few to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized that directly targeting neuroinflammation by downregulating the transcription factor, NF-κB, and the inflammasome protein, NLRP3, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, nontoxic, and effective inhibitors of both NF-κB and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess the aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-κB and NLRP3 downregulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened the lifespan of prion-diseased mice. We have identified a nontoxic, systemic pharmacologic that downregulates NF-κB and NLRP3, prevents neuronal death, and slows the progression of neurodegenerative diseases. Though mouse models do not always predict human patient success and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on the success in a murine prion model, we will continue testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimer’s disease and Parkinson’s disease.

中文翻译：

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通过药物下调炎症途径来靶向神经炎症对蛋白质错误折叠疾病具有神经保护作用

神经炎症在神经退行性蛋白质错误折叠疾病的发展中起着至关重要的作用。此类进行性疾病包括但不限于阿尔茨海默病、帕金森病和朊病毒病。共同的发病机制涉及错误折叠蛋白质的积累、慢性神经炎症和突触功能障碍，最终导致不可逆的神经元损失、可测量的认知缺陷和死亡。目前，几乎没有有效的治疗方法可以阻止神经退行性疾病的发展。我们假设通过下调转录因子 NF-κB 和炎性体蛋白 NLRP3 直接靶向神经炎症将具有神经保护作用。为了实现这一目标，我们使用了一种 RNA 靶向疗法混合物 (SB_NI_112)，该疗法被证明是脑渗透性、无毒且有效的 NF-κB 和 NLRP3 抑制剂。我们利用小鼠适应的朊病毒株作为神经退行性疾病的模型来评估错误折叠蛋白的聚集、神经胶质炎症、神经元损失、认知缺陷和寿命。用SB_NI_112腹膜内或鼻内治疗感染朊病毒的小鼠。 NF-κB 和 NLRP3 下调因子的组合可显着保护行为和认知缺陷。治疗减少了神经胶质炎症，防止神经元损失，防止海绵体变化，挽救认知缺陷，并显着延长患有朊病毒的小鼠的寿命。我们已经确定了一种无毒的全身药理学，可以下调 NF-κB 和 NLRP3、防止神经元死亡并减缓神经退行性疾病的进展。尽管小鼠模型并不总能预测人类患者的成功，并且由于样本量和所使用的给药方法的数量，该研究受到限制，但这些发现为继续将 SB_NI_112 治疗朊病毒病和其他神经退行性疾病的治疗方法转化为原理证明。基于小鼠朊病毒模型的成功，我们将继续在多种神经退行性疾病模型中测试 SB_NI_112，包括阿尔茨海默病和帕金森病。