Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.

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.