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。

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