Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

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 ( Plp1 jp ) 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.