Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints.
Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints.
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朊病毒蛋白降低是一种跨越朊病毒疾病阶段、菌株和终点的疾病修饰疗法。
DOI：
10.1093/nar/gkaa616
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发表时间：
2020-11-04
影响因子：
14.9
通讯作者：
Vallabh SM
中科院分区：
文献类型：
--
作者：
Minikel EV;Zhao HT;Le J;O'Moore J;Pitstick R;Graffam S;Carlson GA;Kavanaugh MP;Kriz J;Kim JB;Ma J;Wille H;Aiken J;McKenzie D;Doh-Ura K;Beck M;O'Keefe R;Stathopoulos J;Caron T;Schreiber SL;Carroll JB;Kordasiewicz HB;Cabin DE;Vallabh SM
朊病毒蛋白（PrP）在大脑中的表达降低是朊病毒疾病的遗传学验证的治疗假设。我们最近发现，反义寡核苷酸（阿索）介导的PrP抑制延长生存期和延迟疾病发作的脑内朊病毒感染的小鼠在预防和延迟给药的范例。在这里，我们研究了这种治疗方法在不同范例中的疗效，改变剂量和给药方案，朊病毒株，治疗时间点，并检查症状，生存和生物标志物读数。我们概括了我们以前的研究结果与额外的PrP靶向ASO，并证明了对四个额外的朊病毒株的治疗效益。我们证明，<25%的PrP抑制足以在预防性范例中延长生存期和延迟症状。在检测到病理变化后，单次给予PrP降低阿索可逆转神经炎症和神经元损伤标志物的升高。慢性ASO介导的PrP抑制在任何时间开始，直到神经病理学的早期迹象，赋予类似于组成性杂合PrP敲除的益处。值得注意的是，即使在出现包括体重减轻在内的明显症状后，一次治疗也会使一部分动物存活数月。这些结果支持ASO介导的PrP降低，以及一般的PrP降低疗法，作为对抗朊病毒疾病的有前途的途径。
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.
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影响因子：
4.6
作者：
Franceschini A;Baiardi S;Hughson AG;McKenzie N;Moda F;Rossi M;Capellari S;Green A;Giaccone G;Caughey B;Parchi P
通讯作者：
Parchi P
影响因子：
4
作者：
Gagnon, Keith T.;Corey, David R.
通讯作者：
Corey, David R.
影响因子：
5.4
作者：
Doh-Ura, K;Ishikawa, K;Iwaki, T
通讯作者：
Iwaki, T
DOI：
10.1073/pnas.1317164110
发表时间：
2013-10-29
影响因子：
11.1
作者：
Berry, David B.;Lu, Duo;Giles, Kurt
通讯作者：
Giles, Kurt
影响因子：
8.8
作者：
Friberg, Karah Nazor;Hung, Gene;Prusiner, Stanley B.
通讯作者：
Prusiner, Stanley B.