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Unraveling Novel Drug candidate for ALS through an Integrative Network Analysis of approved Drug-Gene Expression Signatures in Human Pluripotent Stem Cell-Based Model

ABSTRACT: Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition. In this study, we evaluated the potential of using human pluripotent stem cells to identify repurposable drug candidates. For this purpose, we treated derivatives from human embryonic stem cells with 50 marketed drugs and we annotated the induced molecular changes by RNA deep sequencing. Focusing on genes previously implicated in monogenic diseases, we identified drugs capable of modulating the expression of PLP1, PMP22, LMNB1 and SQSTM1 genes known to be involved in Pelizaeus-Merzbacher disease (PMP), hereditary neuropathy with liability to pressure palsies (HNPP), adult-onset autosomal dominant leukodystrophy (ALDL) and amyotrophic lateral sclerosis (ALS).

ORGANISM(S): Homo sapiens

PROVIDER: GSE261648 | GEO | 2026/06/22

REPOSITORIES: GEO

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Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.

Project description:The leukodystrophy Pelizaeus-Merzbacher disease (PMD) is caused by myelin protein proteolipid protein gene (PLP1) mutations. PMD is characterized by oligodendrocyte death and CNS hypomyelination; thus, increasing oligodendrocyte survival and enhancing myelination could provide therapeutic benefit. Here, we use the PMD mouse model Jimpy to determine the impact of the integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression. Male Jimpy animals in which the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase, protein kinase-like endoplasmic reticulum kinase (PERK), is inactivated have an extended lifespan that correlates with increased oligodendrocyte survival and enhanced CNS myelination. Inactivation of downstream components of the ISR pathway, in contrast, does not rescue oligodendrocytes or myelin. Phosphorylated eIF2α inhibits the exchange factor eIF2B, resulting in diminished protein synthesis. Treatment with small molecule eIF2B activators 2BAct and ISRIB increases oligodendrocyte survival, CNS myelination, and doubled the Jimpy lifespan. These results suggest that ISR modulation could provide therapeutic benefit to PMD patients.

2025-11-07 | GSE277705 | GEO

Chemical chaperone screening for Pelizaeus-Merzbacher disease

Project description:Chemical chaperone screening for Pelizaeus-Merzbacher disease

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Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication

Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals M-bM-^@M-^S 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homologyM-bM-^@M-^Tor homeologyM-bM-^@M-^Tdriven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model. To determine size, genomic extent and gene content for each rearrangement, we used a customized tiling-path oligonucleotide microarray spanning the Xq22 chromosomal region to query the genomic DNA of 7 males with Pelizaeus-Merzbacher disease, and 5 unaffected or carrier/unaffected family members. A 4x44k Agilent Technologies (Santa Clara, CA) microarray was designed using the Agilent e-array website targeting the region of the genome encompassing the dosage-sensitive PLP1 gene.

2014-11-25 | E-GEOD-63594 | biostudies-arrayexpress

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Project description:Progesterone Antagonist Therapy in a Pelizaeus-Merzbacher Mouse Mode

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High-resolution custom array spanning Xq22 region to study patients carrying PLP1 copy number gain

Project description:We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array and breakpoint junction sequence analysis. Analysis of these data enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated. Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array and breakpoint junction sequence analysis.

2019-10-09 | GSE138542 | GEO

Project description:Detection of copy number variation in patients with Pelizaeus-Merzbacher disease (PMD)

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Homo sapiens

Project description:Detection of copy number variation in patients with Pelizaeus-Merzbacher disease (PMD) - Affymetrix

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Project description:Detection of copy number variation in patients with Pelizaeus-Merzbacher disease (PMD) - NimbleGen

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Glycosylation Limits Forward Trafficking of the Tetraspan Membrane Protein PMP22

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2021-04-27 | PXD023091 | Pride

Transcriptomic RNAseq drug screen in cerebrocortical cultures; towards novel neurogenetic disease therapies.

Project description:Rare monogenic diseases affect millions worldwide; although over 4,500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential. To identify such agents for neurogenetic diseases, we have generated genome-wide transcriptome profiles of mouse primary cerebrocortical cultures grown in the presence of 218 blood brain barrier penetrant clinic-tested drugs. RNAseq and differential expression analyses were used to generate transcriptomic profiles; therapeutically relevant drug-gene interactions related to rare neurogenetic diseases identified in this fashion were further analyzed by qRT-PCR, western blot and immunofluorescence. We have created a transcriptome-wide searchable database for easy access to the gene expression data resulting from the cerebrocortical drug screen (Neuron Screen) and have mined this data to identify a novel link between thyroid hormone and expression of the peripheral neuropathy associated gene Pmp22. Our results demonstrate the utility of cerebrocortical cultures for transcriptomic drug screening, and the database we have created will foster further discovery of novel links between over 200 clinic-tested blood brain barrier penetrant drugs and genes related to diverse neurologic conditions.

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