Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease

Elitt, Matthew S.; Shick, H. Elizabeth; Madhavan, Mayur; Allan, Kevin; Clayton, Benjamin L.L.; Weng, Chen; Miller, Tyler E.; Factor, Daniel C.; Barbar, Lilianne; Nawash, Baraa S.; Nevin, Zachary S.; Lager, Angela M.; Li, Yan; Jin, Fulai; Adams, Drew J.; Tesar, Paul J.

doi:10.1016/j.stemcr.2018.07.015

Cited by 33 publications

(34 citation statements)

References 52 publications

(67 reference statements)

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“…4c, d) were stimulated to differentiate towards an oligodendrocyte fate by addition of thyroid hormone, and MBP+ oligodendrocytes were quantified. As expected 22 , jimpy cultures contained only rare surviving MBP+ oligodendrocytes with a concomitant loss in total cells (Fig. 3a-c).…”

Section: Main Textsupporting

confidence: 84%

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Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Elitt¹,

Barbar²,

He³

et al. 2018

Preprint

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14 15 Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe 16 neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher 17 disease (PMD). The majority of PLP1 variants, including supernumerary copies and various 18 point mutations, lead to early mortality. However, PLP1-null patients and mice display 19 comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression 20 might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 21 mediated germline knockdown of Plp1 in the severe jimpy (Plp1 jp ) point mutation mouse 22 model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor 23 function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a 24 therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal 25 PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 26 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted 27 ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and 28 extended lifespan through an 8-month endpoint. Collectively, these results support the 29 development of PLP1 suppression as a disease-modifying therapy for most PMD patients. 30 More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes 31 in vivo to modulate neurological function and lifespan, opening a new treatment modality for 32 myelin disorders. 33 2 Main text: 34 Pelizaeus-Merzbacher disease (PMD; OMIM 312080) is an X-linked leukodystrophy 35 typified by extensive hypomyelination of the central nervous system (CNS). Symptoms typically 36 present early in childhood with a constellation of nystagmus, spasticity, hypotonia, and cognitive 37 dysfunction, leading to mortality in early adulthood. In severe forms, symptoms present connatally 38 and patients succumb to their disease in early childhood. Despite intense interest in PMD 39 therapeutic development, including several clinical trials, no disease modifying therapies have 40 proven efficacious in patients 1-6 . 41 Mutations in the proteolipid protein 1 (PLP1; OMIM 300401) gene underlie the 42 pathogenesis of PMD, with variability in disease onset and progression dictated by the severity of 43 the particular mutation 7-9 . PLP1 codes for the tetraspan protein PLP as well as its shorter splice 44 isoform DM20, which lacks 35 amino acids in the cytosolic loop region 10 . PLP/DM20 is highly 45 conserved across species, with human, mouse, and rat sharing identical amino acid sequence 11 . 46 Expression of PLP1 is largely restricted to myelinating oligodendrocytes, where it is responsible 47 53 15 . Null patients can live until 40-60 years old 8,16 , do not develop lower body spastic paraparesis 54 until the second or third decade of life, and do not demonstrate cognitive regression until the third 55 or fourth decade of life (see Extended Data Table 1 for detailed clinical present...

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Section: Main Textsupporting

confidence: 84%

“…CR- impy iPSCs were derived and characterized for this study (line identifier jpCR100.1). Isogenic comparator jimpy (line identifier i.jp-1.6) and wild-type (line identifier i.wt-1.0) iPSC lines were described and characterized separately 22 . Genotypes of iPSCs were re-verified prior to use.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Elitt¹,

Barbar²,

He³

et al. 2018

Preprint

Self Cite

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“…As examples, Fu et al used PLLA fibers to investigate the unique microtubule biology in oligodendrocytes, while Weightman et al demonstrated that OPCs rely on the presence of astrocytes to survive and elongate on a 3D fibrous scaffold [ 211 , 212 ]. Others have used electrospun fibers to investigate the oligodendroglial pathobiology of CNS diseases, such as multiple sclerosis, perinatal brain injury, Pelizaeus–Merzbacher disease, and Alexander disease [ 213 , 214 , 215 , 216 ]. Additionally, these fibrous scaffolds have been used to screen for potential therapeutics that target underlying molecular mechanisms relating to myelination in CNS disease.…”

Section: Central Nervous Systemmentioning

confidence: 99%

“…Additionally, these fibrous scaffolds have been used to screen for potential therapeutics that target underlying molecular mechanisms relating to myelination in CNS disease. Using electrospun fiber model systems, various molecules have already been screened and shown to reduce OPC stress-related death, improve oligodendrocyte maturation, and reverse demyelinating processes [ 215 , 217 , 218 , 219 ]. For this reason, electrospun fibers will continue to be used as they provide a facile and reproducible myelinating assay [ 220 ].…”

Section: Central Nervous Systemmentioning

confidence: 99%

Electrospun Fiber Scaffolds for Engineering Glial Cell Behavior to Promote Neural Regeneration

et al. 2020

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Electrospinning is a fabrication technique used to produce nano- or micro- diameter fibers to generate biocompatible, biodegradable scaffolds for tissue engineering applications. Electrospun fiber scaffolds are advantageous for neural regeneration because they mimic the structure of the nervous system extracellular matrix and provide contact guidance for regenerating axons. Glia are non-neuronal regulatory cells that maintain homeostasis in the healthy nervous system and regulate regeneration in the injured nervous system. Electrospun fiber scaffolds offer a wide range of characteristics, such as fiber alignment, diameter, surface nanotopography, and surface chemistry that can be engineered to achieve a desired glial cell response to injury. Further, electrospun fibers can be loaded with drugs, nucleic acids, or proteins to provide the local, sustained release of such therapeutics to alter glial cell phenotype to better support regeneration. This review provides the first comprehensive overview of how electrospun fiber alignment, diameter, surface nanotopography, surface functionalization, and therapeutic delivery affect Schwann cells in the peripheral nervous system and astrocytes, oligodendrocytes, and microglia in the central nervous system both in vitro and in vivo. The information presented can be used to design and optimize electrospun fiber scaffolds to target glial cell response to mitigate nervous system injury and improve regeneration.

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“…It is not unlikely that the selective loss or deposition of myelin in specific brain regions, such as occurs in Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity (HBSL) (Taft et al, 2013 ; Fröhlich et al, 2018 ), is driven by a dysfunction of multiple brain cell types. For these reasons brain organoids in which these critical cooperative cell types are appropriately produced are valuable tools for studying (de)-myelination in health and disease states and constitute potential drug testing platforms for diseases that affect myelination, such as Pelizaeus-Merzbacher disease (Elitt et al, 2018 ; Nobuta et al, 2019 ) and HBLS.…”

Section: Discussionmentioning

confidence: 99%

Rapid and Efficient Generation of Myelinating Human Oligodendrocytes in Organoids

Shaker

Pietrogrande

Martin

et al. 2021

Front. Cell. Neurosci.

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Human stem cell derived brain organoids are increasingly gaining attention as an ideal model system for investigating neurological diseases, particularly those that involve myelination defects. However, current protocols for generating brain organoids with sufficiently mature oligodendrocytes that deposit myelin on endogenously produced neurons are lengthy and complicated. Taking advantage of a human pluripotent stem cell line that reports on SOX10 expression, we developed a protocol that involves a 42 day exposure of neuroectoderm-derived organoids to a cocktail of growth factors and small molecules that collectively foster oligodendrocyte specification and survival. Importantly, the resulting day 42 brain organoids contain both myelinating oligodendrocytes, cortical neuronal cells and astrocytes. These oligodendrocyte brain organoids therefore constitute a valuable and tractable platform for functional neurogenomics and drug screening for white matter diseases.

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Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease

Cited by 33 publications

References 52 publications

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Electrospun Fiber Scaffolds for Engineering Glial Cell Behavior to Promote Neural Regeneration

Rapid and Efficient Generation of Myelinating Human Oligodendrocytes in Organoids

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