RARE DISEASE
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease
Synonyms: Diffuse familial brain sclerosis, PMD, Pelizaeus-Merzbacher brain sclerosis, Sudanophilic leukodystrophy, Paelizeus-Merzbacher type
Synonyms: Diffuse familial brain sclerosis, PMD, Pelizaeus-Merzbacher brain sclerosis, Sudanophilic leukodystrophy, Paelizeus-Merzbacher type
Synonyms: Diffuse familial brain sclerosis, PMD, Pelizaeus-Merzbacher brain sclerosis, Sudanophilic leukodystrophy, Paelizeus-Merzbacher type
Drug discovery
2
drugs
With orphan designations
Overview
Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by PLP1 gene mutations, disrupting myelin formation in the central nervous system. It primarily affects males, presenting with nystagmus, hypotonia, ataxia, and progressive spasticity. PMD manifests as classic (developmental delay with partial myelination) or severe connatal forms (neonatal onset, minimal myelination). Hypomyelination leads to motor and cognitive impairment, with lifespan ranging from childhood to adulthood depending on severity [1][4][16].
Therapies
Supportive care: Physical therapy, antispasticity agents (baclofen), gastrostomy for dysphagia, and seizure management [4][7][9].
Emerging therapies: Antisense oligonucleotides to reduce toxic PLP1 protein [3][11], ketogenic diets to support oligodendrocyte function [4], and neural stem cell transplantation trials [5][19].
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
133 drug discovery papers about Pelizaeus-Merzbacher disease, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
133 drug discovery papers about Pelizaeus-Merzbacher disease, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Pelizaeus-Merzbacher disease in a manifesting female carrier with a PLP1 frameshift variant: neuroimaging and neurophysiological findings
The Annals of Clinical Neurophysiology (ACN), the joint official journal of The Korean Society of Clinical Neurophysiology and The Korean Society of Pain & Autonomic Disorders, publishes twice a year on April 30 and October 31 in English.
2026-08-03 | Gap junction protein gamma 2 (GJC2) gene frameshift deletion in Toy Poodles with hypomyelinating leukodystrophy resembling human Pelizaeus-Merzbacher-like disease 1.
Pelizaeus-Merzbacher-like disease type 1 (PMLD1), also known as hypomyelinating dystrophy 2, is a typical slowly progressive hypomyelinating leukodystrophy (HLD) that manifests in the neonatal period or early infancy. In humans, PMLD1 is inherited as an autosomal recessive trait, with genetic variants identified in the gap junction protein gamma 2 (GJC2) gene. Six juvenile-age Toy Poodle dogs exhibited coarse, vertical head and trunk tremors from immediately after birth. Conventional magnetic resonance imaging revealed uniform signal hyperintensities throughout the subcortical white matter in all dogs. All dogs were euthanized. Subsequent histopathological examination revealed vacuolar changes and demyelination in the cerebral and cerebellar white matter, leading to a diagnosis of HLD. Genetic analysis of five affected dogs identified a shared homozygous 14-base pair deletion in the GJC2 gene, XM_038556433.1:c.920_933del. To the best of our knowledge, this is the first report of a pathogenic GJC2 variant in dogs or any other domestic animal species. The results will enable genetic testing and provide a spontaneous large animal model for the homologous human disease.
2026-02-27 | Mutant PLP1 impairs COPII vesicle formation via ER calcium depletion in Pelizaeus-Merzbacher disease.
Pelizaeus-Merzbacher disease (PMD) is a devastating, X-linked hypomyelinating leukodystrophy caused by mutations in a myelin gene, PLP1. While overwhelming endoplasmic reticulum (ER) stress caused by the accumulation of mutant PLP1 is widely recognized, blockade of the apoptotic arm of the unfolded protein response (UPR) failed to rescue the phenotypes in murine disease models, suggesting the involvement of additional, critical cellular mechanisms in oligodendrocyte dysfunction. Herein, we identified ER Ca2+ depletion and disrupted ER-Golgi trafficking as key cellular pathologies in PMD. Mutant PLP1 impairs COPII vesicle formation by destabilizing its key components, including Sec31A at ER exit sites due to the Ca2+ transport dysregulation and deconstruction of the ALG-2/Sec31A/AnxA11 interaction. Pharmacological restoration of ER Ca2+ levels rescued COPII formation. These findings highlight how PLP1 mutations affect the intracellular trafficking of membrane and secretory proteins through the ER Ca2+ depletion, which may be associated with the clinical consequences of PMD and other inherited myelin disorders.
2026-02-25 | Spatially concentrated adenine base editors efficiently correct PLP1 mutations in oligodendrocytes.
Oligodendrocytes (OLs), the myelinating cells of the central nervous system, are particularly prone to pathogenic G-to-A mutations, such as PLP1A243V, which causes Pelizaeus-Merzbacher disease (PMD), a lethal hypomyelinating disorder lacking effective therapy. Although adenine base editors (ABEs) can in principle correct such mutations, their application in OLs is limited by inefficient on-target editing. Here, we develop a spatially concentrated ABE (cABE) strategy that enhances editing by promoting nuclear translocation of tRNA adenosine deaminase (TadA*) from the cytoplasm. Using a SunTag-based multivalent recruitment system, TadA* is locally enriched at genomic targets (cABE-1.0), achieving robust editing in vitro. To enable in vivo delivery while preserving high efficiency and fidelity, SpCas9 is replaced with compact eNme2-C Cas9, generating an AAV-compatible variant (cABE-2.0). Notably, cABE-2.0 forms dynamic nuclear puncta with properties of liquid-liquid phase separation, enhancing on-target editing while substantially reducing transcriptome-wide RNA off-target effects. Functionally, cABE-2.0 efficiently corrects the PLP1A243V mutation in OLs, restores Plp subcellular localization, and rescues myelination-related phenotypes. These findings demonstrate that spatial reorganization, rather than increasing intrinsic catalytic activity of TadA*, provides a distinct principle for improving base editing in difficult-to-edit cell types, such as OLs, offering a mechanistic and technical framework for gene therapy of PMD and related myelin disorders.
2025-12-27 | Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.
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.
2026-08-11 | Pelizaeus-Merzbacher disease in a manifesting female carrier with a PLP1 frameshift variant: neuroimaging and neurophysiological findings
The Annals of Clinical Neurophysiology (ACN), the joint official journal of The Korean Society of Clinical Neurophysiology and The Korean Society of Pain & Autonomic Disorders, publishes twice a year on April 30 and October 31 in English.
2026-08-03 | Gap junction protein gamma 2 (GJC2) gene frameshift deletion in Toy Poodles with hypomyelinating leukodystrophy resembling human Pelizaeus-Merzbacher-like disease 1.
Pelizaeus-Merzbacher-like disease type 1 (PMLD1), also known as hypomyelinating dystrophy 2, is a typical slowly progressive hypomyelinating leukodystrophy (HLD) that manifests in the neonatal period or early infancy. In humans, PMLD1 is inherited as an autosomal recessive trait, with genetic variants identified in the gap junction protein gamma 2 (GJC2) gene. Six juvenile-age Toy Poodle dogs exhibited coarse, vertical head and trunk tremors from immediately after birth. Conventional magnetic resonance imaging revealed uniform signal hyperintensities throughout the subcortical white matter in all dogs. All dogs were euthanized. Subsequent histopathological examination revealed vacuolar changes and demyelination in the cerebral and cerebellar white matter, leading to a diagnosis of HLD. Genetic analysis of five affected dogs identified a shared homozygous 14-base pair deletion in the GJC2 gene, XM_038556433.1:c.920_933del. To the best of our knowledge, this is the first report of a pathogenic GJC2 variant in dogs or any other domestic animal species. The results will enable genetic testing and provide a spontaneous large animal model for the homologous human disease.
2026-02-27 | Mutant PLP1 impairs COPII vesicle formation via ER calcium depletion in Pelizaeus-Merzbacher disease.
Pelizaeus-Merzbacher disease (PMD) is a devastating, X-linked hypomyelinating leukodystrophy caused by mutations in a myelin gene, PLP1. While overwhelming endoplasmic reticulum (ER) stress caused by the accumulation of mutant PLP1 is widely recognized, blockade of the apoptotic arm of the unfolded protein response (UPR) failed to rescue the phenotypes in murine disease models, suggesting the involvement of additional, critical cellular mechanisms in oligodendrocyte dysfunction. Herein, we identified ER Ca2+ depletion and disrupted ER-Golgi trafficking as key cellular pathologies in PMD. Mutant PLP1 impairs COPII vesicle formation by destabilizing its key components, including Sec31A at ER exit sites due to the Ca2+ transport dysregulation and deconstruction of the ALG-2/Sec31A/AnxA11 interaction. Pharmacological restoration of ER Ca2+ levels rescued COPII formation. These findings highlight how PLP1 mutations affect the intracellular trafficking of membrane and secretory proteins through the ER Ca2+ depletion, which may be associated with the clinical consequences of PMD and other inherited myelin disorders.
2026-02-25 | Spatially concentrated adenine base editors efficiently correct PLP1 mutations in oligodendrocytes.
Oligodendrocytes (OLs), the myelinating cells of the central nervous system, are particularly prone to pathogenic G-to-A mutations, such as PLP1A243V, which causes Pelizaeus-Merzbacher disease (PMD), a lethal hypomyelinating disorder lacking effective therapy. Although adenine base editors (ABEs) can in principle correct such mutations, their application in OLs is limited by inefficient on-target editing. Here, we develop a spatially concentrated ABE (cABE) strategy that enhances editing by promoting nuclear translocation of tRNA adenosine deaminase (TadA*) from the cytoplasm. Using a SunTag-based multivalent recruitment system, TadA* is locally enriched at genomic targets (cABE-1.0), achieving robust editing in vitro. To enable in vivo delivery while preserving high efficiency and fidelity, SpCas9 is replaced with compact eNme2-C Cas9, generating an AAV-compatible variant (cABE-2.0). Notably, cABE-2.0 forms dynamic nuclear puncta with properties of liquid-liquid phase separation, enhancing on-target editing while substantially reducing transcriptome-wide RNA off-target effects. Functionally, cABE-2.0 efficiently corrects the PLP1A243V mutation in OLs, restores Plp subcellular localization, and rescues myelination-related phenotypes. These findings demonstrate that spatial reorganization, rather than increasing intrinsic catalytic activity of TadA*, provides a distinct principle for improving base editing in difficult-to-edit cell types, such as OLs, offering a mechanistic and technical framework for gene therapy of PMD and related myelin disorders.
2025-12-27 | Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Pelizaeus-Merzbacher disease.
2 orphan drug designations for Pelizaeus-Merzbacher disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting PLP1 pre-mRNA | oligonucleotides | FDA | 2023-09-15 | — | Ionis Pharmaceuticals, Inc. |
2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting PLP1 pre-mRNA | oligonucleotides | EMA | 2023-08-16 | — | Ionis Development (Ireland) Limited |
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