Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

In a mouse model of the leukodystrophy Pelizaeus-Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggestingPLP1as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders. Mutations inPLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)(1,2). MostPLP1mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lackPLP1expression, andPlp1-null mice, can display comparatively mild phenotypes, suggesting thatPLP1suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show, using CRISPR-Cas9 to suppressPlp1expression in thejimpy(Plp1(jp)) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels ofPlp1mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose ofPlp1-targeting antisense oligonucleotides in postnataljimpymice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest thatPLP1suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.