小柯机器人

抑制蛋白脂蛋白可治疗佩梅病
2020-07-04 17:22

近日,美国凯斯西储大学医学院Paul J. Tesar课题组发现,抑制蛋白脂蛋白可治疗佩梅病(Pelizaeus-Merzbacher disease,PMD)。该项研究成果于2020年7月1日在线发表在《自然》杂志上。

据研究人员介绍,蛋白脂蛋白1(PLP1)的突变在X染色体连锁性白质营养不良的PMD中导致髓鞘衰竭和神经功能障碍。大多数PLP1突变,包括点突变和多余的拷贝变异,都会导致严重和致命的疾病。然而,无PLP1的患者和小鼠可以表现出相对较轻的表型,这表明PLP1的抑制可能为PMD1提供通用的治疗策略。
 
研究人员在PMD的严重jimpy(Plp1jp)点突变小鼠模型中显示了有效的体内Plp1抑制。CRISPR-Cas9介导的对Jimpy小鼠Plp1的生殖系抑制可增加髓鞘形成并将神经传导速度、运动功能和寿命恢复至野生型水平,从而证实PLP1抑制是一种治疗方法。为了评估该策略的转化潜力,研究人员在体内鉴定了在整个神经元中都能稳定降低Plp1 mRNA和蛋白质的反义寡核苷酸(ASO)。给予产后jimpy小鼠单剂量靶向Plp1的ASO可以完全恢复少突胶质细胞的数量,增加髓鞘形成,改善运动功能,使呼吸功能正常化并延长寿命。
 
这些结果表明,开发PLP1抑制疗法可用于治疗PMD。更广泛地说,研究人员证明了寡核苷酸治疗剂可以在体内传递到少突胶质细胞中,进而调节神经功能和寿命,为髓磷脂疾病建立新的药物治疗方式。
 
附:英文原文

Title: Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

Author: Matthew S. Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-Hikichi, Mayur Madhavan, Kevin C. Allan, Baraa S. Nawash, Artur S. Gevorgyan, Stevephen Hung, Zachary S. Nevin, Hannah E. Olsen, Midori Hitomi, Daniela M. Schlatzer, Hien T. Zhao, Adam Swayze, David F. LePage, Weihong Jiang, Ronald A. Conlon, Frank Rigo, Paul J. Tesar

Issue&Volume: 2020-07-01

Abstract: Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and neurological dysfunction in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. PLP1-null patients and mice, however, can display comparatively mild phenotypes, suggesting that PLP1-suppression might provide a general therapeutic strategy for PMD1,3–5. Here we show effective in vivo Plp1-suppression in the severe jimpy (Plp1jp) point mutation mouse model of PMD. CRISPR-Cas9 mediated germline suppression of Plp1 in jimpy mice increased myelination and restored nerve conduction velocity, motor function, and lifespan to wild-type levels, validating PLP1-suppression as a therapeutic approach. To evaluate the translational potential of this strategy we identified antisense oligonucleotides (ASOs) that stably decrease Plp1 mRNA and protein throughout the neuraxis, in vivo. Administration of a single dose of Plp1-targeting ASOs to postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function, and extended lifespan through an 8-month endpoint. These results support the development of PLP1-suppression as a treatment for PMD. More broadly, we demonstrate that oligonucleotide therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.

DOI: 10.1038/s41586-020-2494-3

Source: https://www.nature.com/articles/s41586-020-2494-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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