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Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

机译：抑制蛋白质蛋白拯救的pelizaeus-merzbacher疾病

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摘要

In a mouse model of the leukodystrophy Pelizaeus-Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggestingPLP1as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.Mutations inPLP1, 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). MostPLP1mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lackPLP1expression, andPlp1-null mice, can display comparatively mild phenotypes, suggesting thatPLP1suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show, using CRISPR-Cas9 to suppressPlp1expression in thejimpy(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 ofPlp1mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose ofPlp1-targeting antisense oligonucleotides in postnataljimpymice 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 thatPLP1suppression 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.
机译：通过抑制蛋白质蛋白表达，提高了髓鞘，电动机性能，呼吸功能和寿命的鼠标模型，提出了人类患者的治疗靶标，更广泛地，反义的寡核苷酸作为药物模态对于髓鞘紊乱的治疗方法Inplp1，编码Proteolipid蛋白（PLP）的基因，导致X-染色体连接的白科医镜术（PMD）（1,2）中的髓鞘髓鞘和神经功能障碍失败（1,2）。大部分，包括点突变和超值拷贝变种，导致严重和致命的疾病。 HASPLP1-NULL小鼠的患者可以显示比较温和的表型，表明该抑制可以为PMD1,3-5提供一般的治疗策略。在这里，我们展示了使用CRISPR-CAS9来抑制JIMPY（PLP1（JP））点突变鼠标模型的严重PMD，增加髓鞘和恢复的神经传导速度，电机功能和小鼠的寿命与野生型水平。为了评估该策略的翻译潜力，我们鉴定了反义寡核苷酸，其稳定地降低在体内整个神经内的PLP1MRNA和PLP蛋白水平。施用单一剂量的OFPLP1靶向反义寡核苷酸在后jimpimimice中完全恢复的少曲细胞数，增加髓鞘，改善电动机性能，归一化呼吸功能，并将寿命延伸到八个月的终点。这些结果表明，可以作为人类的PMD的治疗方式发展。更广泛地，我们证明基于寡核苷酸的治疗剂可以递送至体内的少突胶质细胞以调节神经功能和寿命，为髓鞘紊乱建立新的药物模型。

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  • 来源
    《Nature》 |2020年第7825期|397-403|共7页
  • 作者

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

  • 作者单位

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Ionis Pharmaceut Carlsbad CA USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Cleveland Clin Lerner Res Inst Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Med Case Ctr Prote & Bioinformat Cleveland OH 44106 USA;

    Ionis Pharmaceut Carlsbad CA USA;

    Ionis Pharmaceut Carlsbad CA USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

    Ionis Pharmaceut Carlsbad CA USA;

    Case Western Reserve Univ Sch Med Dept Genet & Genome Sci Cleveland OH 44106 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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