TY - JOUR
T1 - Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease
AU - Elitt, Matthew S.
AU - Barbar, Lilianne
AU - Shick, H. Elizabeth
AU - Powers, Berit E.
AU - Maeno-Hikichi, Yuka
AU - Madhavan, Mayur
AU - Allan, Kevin C.
AU - Nawash, Baraa S.
AU - Gevorgyan, Artur S.
AU - Hung, Stevephen
AU - Nevin, Zachary S.
AU - Olsen, Hannah E.
AU - Hitomi, Midori
AU - Schlatzer, Daniela M.
AU - Zhao, Hien T.
AU - Swayze, Adam
AU - LePage, David F.
AU - Jiang, Weihong
AU - Conlon, Ronald A.
AU - Rigo, Frank
AU - Tesar, Paul J.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/9/17
Y1 - 2020/9/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087303118&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2494-3
DO - 10.1038/s41586-020-2494-3
M3 - Article
C2 - 32610343
AN - SCOPUS:85087303118
SN - 0028-0836
VL - 585
SP - 397
EP - 403
JO - Nature
JF - Nature
IS - 7825
ER -