Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease

Matthew S. Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-Hikichi, Mayur Madhavan, Kevin C. Allan, Baraa S. Nawash, Artur S. Gevorgyan, Stevephen Hung, Zachary S. Nevin, Hannah E. Olsen, Midori Hitomi, Daniela M. Schlatzer, Hien T. Zhao, Adam Swayze, David F. LePage, Weihong Jiang, Ronald A. Conlon, Frank Rigo and Paul J. Tesar ()
Additional contact information
Matthew S. Elitt: Case Western Reserve University School of Medicine
Lilianne Barbar: Case Western Reserve University School of Medicine
H. Elizabeth Shick: Case Western Reserve University School of Medicine
Berit E. Powers: Ionis Pharmaceuticals
Yuka Maeno-Hikichi: Case Western Reserve University School of Medicine
Mayur Madhavan: Case Western Reserve University School of Medicine
Kevin C. Allan: Case Western Reserve University School of Medicine
Baraa S. Nawash: Case Western Reserve University School of Medicine
Artur S. Gevorgyan: Case Western Reserve University School of Medicine
Stevephen Hung: Case Western Reserve University School of Medicine
Zachary S. Nevin: Case Western Reserve University School of Medicine
Hannah E. Olsen: Case Western Reserve University School of Medicine
Midori Hitomi: Cleveland Clinic
Daniela M. Schlatzer: Case Western Reserve University School of Medicine
Hien T. Zhao: Ionis Pharmaceuticals
Adam Swayze: Ionis Pharmaceuticals
David F. LePage: Case Western Reserve University School of Medicine
Weihong Jiang: Case Western Reserve University School of Medicine
Ronald A. Conlon: Case Western Reserve University School of Medicine
Frank Rigo: Ionis Pharmaceuticals
Paul J. Tesar: Case Western Reserve University School of Medicine

Nature, 2020, vol. 585, issue 7825, 397-403

Abstract: Abstract 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 PMD1,3–5. Here we show, using CRISPR–Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) 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.

Date: 2020
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DOI: 10.1038/s41586-020-2494-3

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