Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.
Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.
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DOI：
10.1038/s41586-020-2494-3
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发表时间：
2020-09
期刊：
影响因子：
64.8
通讯作者：
Tesar PJ
中科院分区：
文献类型：
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作者：
Elitt MS;Barbar L;Shick HE;Powers BE;Maeno-Hikichi Y;Madhavan M;Allan KC;Nawash BS;Gevorgyan AS;Hung S;Nevin ZS;Olsen HE;Hitomi M;Schlatzer DM;Zhao HT;Swayze A;LePage DF;Jiang W;Conlon RA;Rigo F;Tesar PJ
蛋白脂蛋白1 （PLP1）突变导致x连锁白质营养不良Pelizaeus-Merzbacher病（PMD）的髓鞘形成失败和神经功能障碍。大多数PLP1突变，包括点突变和额外拷贝变异，会导致严重和致命的疾病。然而，plp1缺失的患者和小鼠可以表现出相对温和的表型，这表明抑制plp1可能为PMD提供了一种通用的治疗策略。我们在PMD小鼠模型中发现了有效的体内plp1抑制。CRISPR-Cas9介导的神经痉挛小鼠种系Plp1抑制增加了髓鞘形成，并将神经传导速度、运动功能和寿命恢复到野生型水平，验证了Plp1抑制作为一种治疗方法。为了评估这一策略的翻译潜力，我们在体内鉴定了反义寡核苷酸（ASOs），它们稳定地降低了整个神经轴的Plp1 mRNA和蛋白。通过8个月的研究，给出生后残疾小鼠单剂量plp1靶向aso完全恢复了少突胶质细胞数量，增加了髓鞘形成，改善了运动表现，恢复了正常的呼吸功能，延长了寿命。这些结果支持plp1抑制作为PMD治疗方法的发展。更广泛地说，我们证明了寡核苷酸疗法可以在体内传递给少突胶质细胞来调节神经功能和寿命，为髓鞘疾病建立了一种新的药物模式。
Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and neurological dysfunction in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). 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 PMD. 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.
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影响因子：
16.2
作者：
Kordasiewicz HB;Stanek LM;Wancewicz EV;Mazur C;McAlonis MM;Pytel KA;Artates JW;Weiss A;Cheng SH;Shihabuddin LS;Hung G;Bennett CF;Cleveland DW
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Charpentier, Emmanuelle
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影响因子：
64.8
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Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
影响因子：
46.9
作者：
通讯作者：
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