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Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease
Matthew S Elitt1, Lilianne Barbar1, H Elizabeth Shick1
1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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.
Insights
Gene therapy targeting PLP1 (proteolipid protein 1) offers a promising treatment for Pelizaeus-Merzbacher disease (PMD). Suppressing PLP1 expression in mouse models restored myelination and neurological function, suggesting a potential therapeutic strategy for PMD.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Mutations in the PLP1 gene cause Pelizaeus-Merzbacher disease (PMD), a severe X-linked leukodystrophy characterized by failed myelination and neurological deficits.
- Most PLP1 mutations lead to severe disease, but complete absence of PLP1 expression results in milder phenotypes, suggesting PLP1 suppression as a therapeutic avenue.
Purpose of the Study:
- To investigate the therapeutic potential of suppressing PLP1 expression in a mouse model of severe PMD.
- To evaluate the efficacy of CRISPR-Cas9 and antisense oligonucleotides in restoring myelination and neurological function.
Main Methods:
- CRISPR-Cas9 was used to suppress Plp1 expression in the jimpy (Plp1^jp) mouse model of PMD.
- Antisense oligonucleotides targeting Plp1 mRNA were developed and administered to postnatal jimpy mice.
- Assessed myelination, nerve conduction velocity, motor function, respiratory function, and lifespan.
Main Results:
- CRISPR-Cas9-mediated Plp1 suppression in jimpy mice increased myelination and restored motor function, nerve conduction velocity, and lifespan to wild-type levels.
- A single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice normalized oligodendrocyte numbers, enhanced myelination, improved motor and respiratory function, and extended lifespan.
- Oligonucleotide delivery to oligodendrocytes in vivo effectively modulated neurological function and lifespan.
Conclusions:
- PLP1 suppression is a viable therapeutic strategy for Pelizaeus-Merzbacher disease.
- Oligonucleotide-based therapies can be delivered to oligodendrocytes to treat myelin disorders, establishing a new pharmaceutical modality.
