Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice
| Autor: | Masahiro Hitomi, Ronald A. Conlon, Berit Powers, Matthew S. Elitt, Baraa S. Nawash, Zachary S. Nevin, Frank Rigo, David F. LePage, H. Elizabeth Shick, Weihong Jiang, Mayur Madhavan, Paul J. Tesar, Hannah E. Olsen, Kevin C. Allan, Lilianne Barbar, Yuka Maeno-Hikichi |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Gene knockdown Proteolipid protein 1 business.industry Point mutation Leukodystrophy Pelizaeus–Merzbacher disease medicine.disease Phenotype 3. Good health 03 medical and health sciences Myelin 0302 clinical medicine medicine.anatomical_structure In vivo medicine Cancer research business 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/508192 |
| Popis: | Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher disease (PMD). The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to early mortality. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 mediated germline knockdown of Plp1 in the severe jimpy (Plp1jp) point mutation mouse model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and extended lifespan through an 8-month endpoint. Collectively, these results support the development of PLP1 suppression as a disease-modifying therapy for most PMD patients. More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, opening a new treatment modality for myelin disorders. |
| Databáze: | OpenAIRE |
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