Mutations in PLP1 , the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD) 1 , 2 . Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1 -null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD 1 , 3 – 5 . Here we show, using CRISPR–Cas9 to suppress Plp1 expression in the jimpy ( Plp1 jp ) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1 -targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders. In a mouse model of the leukodystrophy Pelizaeus–Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

中文翻译：

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抑制蛋白脂蛋白可挽救 Pelizaeus-Merzbacher 病

PLP1 是编码蛋白脂蛋白 (PLP) 的基因，其突变会导致 X 染色体相关的脑白质营养不良症 (PMD) 1、2 中的髓鞘形成失败和神经功能障碍。大多数 PLP1 突变，包括点突变和多余的拷贝变体，会导致严重和致命的疾病。缺乏 PLP1 表达的患者和 Plp1 缺失小鼠可以表现出相对温和的表型，这表明 PLP1 抑制可能为 PMD 1 、 3 – 5 提供一般治疗策略。在这里，我们展示了使用 CRISPR-Cas9 抑制严重 PMD 的 jimpy ( Plp1 jp ) 点突变小鼠模型中的 Plp1 表达，增加髓鞘形成并将小鼠的神经传导速度、运动功能和寿命恢复到野生型水平。为了评估该策略的转化潜力，我们鉴定了反义寡核苷酸，可稳定降低体内整个神经轴的 Plp1 mRNA 和 PLP 蛋白的水平。在出生后的 jimpy 小鼠中施用单剂量 Plp1 靶向反义寡核苷酸可完全恢复少突胶质细胞数量、增加髓鞘形成、改善运动性能、使呼吸功能正常化并将寿命延长至八个月。这些结果表明，PLP1 抑制可以开发为人类 PMD 的治疗方法。更广泛地说，我们证明了基于寡核苷酸的治疗剂可以在体内递送到少突胶质细胞以调节神经功能和寿命，从而为髓鞘疾病建立新的药物模式。在脑白质营养不良 Pelizaeus-Merzbacher 病的小鼠模型中，髓鞘形成、运动表现、