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Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

AbstractMutations 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.

Author informationAffiliationsDepartment of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106, USAMatthew S. Elitt, Lilianne Barbar, H. Elizabeth Shick, Yuka Maeno-Hikichi, Mayur Madhavan, Kevin C. Allan, Baraa S. Nawash, Artur S. Gevorgyan, Stevephen Hung, Zachary S. Nevin, Hannah E. Olsen, David F. LePage, Weihong Jiang, Ronald A. Conlon & Paul J. TesarIonis Pharmaceuticals, Carlsbad, California, 92008, USABerit E. Powers, Hien T. Zhao, Adam Swayze & Frank RigoLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44106, USAMidori HitomiCase Center for Proteomics and Bioinformatics, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106, USADaniela M. SchlatzerCorresponding authorCorrespondence to
Paul J. Tesar.Supplementary information

41586_2020_2494_MOESM3_ESM.mp4| Plp1 suppression in jimpy mice rescues neurological phenotypes at 3 weeks of age Video comparison of wild-type, jimpy, and CR-impy mice at 3 weeks of age. Representative videos of n=25, 20, 12 wild-type, CR-impy, and jimpy mice, respectively.
41586_2020_2494_MOESM4_ESM.mp4| Plp1 suppression in jimpy mice shows sustained rescue of neurological phenotypes at 18 months of age Video comparison of wild-type and CR-impy mice at 18 months of age (study endpoint). Representative videos of n=4, 5 wild-type and CR-impy mice, respectively.
41586_2020_2494_MOESM5_ESM.mp4| Postnatal delivery of Plp1-targeted ASOs to jimpy mice rescues neurological phenotypes at 3 weeks of age Video comparison of wild-type and jimpy mice injected with control and Plp1-targeting ASOs at 3 weeks of age. Representative videos of n=5, 5, 8 uninjected wild-type, jpASOPlp1.a, and jpASOPlp1.b mice, respectively.
41586_2020_2494_MOESM6_ESM.mp4| Postnatal delivery of Plp1-targeted ASOs to jimpy mice shows sustained rescue of neurological phenotypes at 6 months of age Video comparison of wild-type and jimpy mice injected with control and Plp1-targeting ASOs at 6 months of age. Representative videos of n=5, 5, 7 uninjected wild-type, jpASOPlp1.a, and jpASOPlp1.b mice, respectively.
Supplementary InformationThis merged pdf file contains Supplementary Tables 1-4, Supplementary Data 1-14, which provide metadata for in vivo studies, uncropped scans of immunoblots, and source immunohistochemical images for cell number quantifications, and supplementary references.Supplementary Video 1| Plp1 suppression in jimpy mice rescues neurological phenotypes at 3 weeks of age Video comparison of wild-type, jimpy, and CR-impy mice at 3 weeks of age. Representative videos of n=25, 20, 12 wild-type, CR-impy, and jimpy mice, respectively.Supplementary Video 2| Plp1 suppression in jimpy mice shows sustained rescue of neurological phenotypes at 18 months of age Video comparison of wild-type and CR-impy mice at 18 months of age (study endpoint). Representative videos of n=4, 5 wild-type and CR-impy mice, respectively.Supplementary Video 3| Postnatal delivery of Plp1-targeted ASOs to jimpy mice rescues neurological phenotypes at 3 weeks of age Video comparison of wild-type and jimpy mice injected with control and Plp1-targeting ASOs at 3 weeks of age. Representative videos of n=5, 5, 8 uninjected wild-type, jpASOPlp1.a, and jpASOPlp1.b mice, respectively.Supplementary Video 4| Postnatal delivery of Plp1-targeted ASOs to jimpy mice shows sustained rescue of neurological phenotypes at 6 months of age Video comparison of wild-type and jimpy mice injected with control and Plp1-targeting ASOs at 6 months of age. Representative videos of n=5, 5, 7 uninjected wild-type, jpASOPlp1.a, and jpASOPlp1.b mice, respectively.About this articleCite this articleElitt, M.S., Barbar, L., Shick, H.E. et al. Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.
Nature (2020). https://doi.org/10.1038/s41586-020-2494-3Download citationReceived: 29 December 2018Accepted: 24 June 2020Published: 01 July 2020DOI: https://doi.org/10.1038/s41586-020-2494-3CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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