Journal Article

Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease

Powers, Berit E., Nawash, Baraa S., LePage, David F., Nevin, Zachary S., Olsen, Hannah E., Elitt, Matthew S., Shick, H. Elizabeth, Gevorgyan, Artur S., Tesar, Paul J., Zhao, Hien T., Barbar, Lilianne, Schlatzer, Daniela M., Maeno-Hikichi, Yuka, Rigo, Frank, Conlon, Ronald A., Hung, Stevephen, Swayze, Adam, Hitomi, Midori, Madhavan, Mayur, Allan, Kevin C., Jiang, Weihong

2020

Overview

Mutations in PLP1 , 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 . Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1 -null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD 1 , 3 – 5 . Here we show, using CRISPR–Cas9 to suppress Plp1 expression in the jimpy ( 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 of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1 -targeting antisense oligonucleotides in postnatal jimpy mice 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 that PLP1 suppression 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. In a mouse model of the leukodystrophy Pelizaeus–Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 13/51 / 38/89 / 631/154/51/1914 / 631/154/556 / 631/378/2606 / 64/60 / Age / Animals / Antisense oligonucleotides / Antisense therapy / Ataxia / Care and treatment / Chemical compounds / Chromosomes / CRISPR-Cas Systems / Development and progression / Disease Models, Animal / Female / Gene Editing / Gene expression / Gene mutations / Genetic aspects / Health aspects / Humanities and Social Sciences / Hypoxia - metabolism / Leukodystrophy / Life span / Male / Mice / Mice, Mutant Strains / Motor Activity - genetics / Motor task performance / mRNA / multidisciplinary / Mutation / Myelin / Myelin proteolipid protein / Myelin Proteolipid Protein - deficiency / Myelin Proteolipid Protein - genetics / Myelin Proteolipid Protein - metabolism / Myelin Sheath - metabolism / Myelination / Nerve conduction / Neuraxis / Neurological complications / Oligodendrocytes / Oligodendroglia - metabolism / Oligonucleotides / Oligonucleotides, Antisense - administration & dosage / Oligonucleotides, Antisense - genetics / Pelizaeus-Merzbacher disease / Pelizaeus-Merzbacher Disease - genetics / Pelizaeus-Merzbacher Disease - metabolism / Pelizaeus-Merzbacher Disease - therapy / Pharmacology / Phenotypes / Point Mutation / Proteins / Respiratory function / Respiratory Function Tests / Rodents / Science / Science (multidisciplinary) / Supernumerary / Survival Analysis