Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Prion Alliance, Cambridge, MA, 02139, USA.
Nucleic Acids Res. 2020 Nov 4;48(19):10615-10631. doi: 10.1093/nar/gkaa616.
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.
降低大脑中朊病毒蛋白（PrP）的表达是朊病毒病的一种经过基因验证的治疗假说。我们最近表明，反义寡核苷酸（ASO）介导的 PrP 抑制可延长脑内感染朊病毒的小鼠的存活时间并延迟疾病发作，无论是在预防性还是延迟性给药方案中。在这里，我们在不同的方案中检查了这种治疗方法的疗效，改变了剂量和给药方案、朊病毒株、治疗时间点，并检查了症状、存活和生物标志物的读数。我们用额外的靶向 PrP 的 ASO 重复了我们之前的发现，并证明了针对另外四种朊病毒株的治疗益处。我们证明，即使 PrP 抑制率低于 25%，也足以在预防性方案中延长存活时间并延迟症状出现。在检测到病理性变化后，单次给予降低 PrP 的 ASO 即可逆转神经炎症和神经元损伤标志物的升高。从任何时间开始到神经病理学早期迹象开始，慢性 ASO 介导的 PrP 抑制与组成型杂合 PrP 敲除具有相似的益处。值得注意的是，即使在出现明显症状（包括体重减轻）后，单次治疗也能使一部分动物的存活时间延长数月。这些结果支持 ASO 介导的 PrP 降低，以及一般的 PrP 降低治疗方法，作为一种有前途的朊病毒病治疗途径。
