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1.
Trends Mol Med ; 30(5): 459-470, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582621

RESUMO

Pelizaeus-Merzbacher disease (PMD) is caused by mutations in the proteolipid protein 1 (PLP1) gene encoding proteolipid protein (PLP). As a major component of myelin, mutated PLP causes progressive neurodegeneration and eventually death due to severe white matter deficits. Medical care has long been limited to symptomatic treatments, but first-in-class PMD therapies with novel mechanisms now stand poised to enter clinical trials. Here, we review PMD disease mechanisms and outline rationale for therapeutic interventions, including PLP1 suppression, cell transplantation, iron chelation, and intracellular stress modulation. We discuss available preclinical data and their implications on clinical development. With several novel treatments on the horizon, PMD is on the precipice of a new era in the diagnosis and treatment of patients suffering from this debilitating disease.


Assuntos
Proteína Proteolipídica de Mielina , Bainha de Mielina , Doença de Pelizaeus-Merzbacher , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/terapia , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/patologia , Humanos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Animais , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Mutação
2.
Development ; 149(20)2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35748297

RESUMO

Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Pelizaeus-Merzbacher , Diferenciação Celular/fisiologia , Fibroblastos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Oligodendroglia/metabolismo , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Doença de Pelizaeus-Merzbacher/terapia
3.
Nature ; 585(7825): 397-403, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610343

RESUMO

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.


Assuntos
Modelos Animais de Doenças , Proteína Proteolipídica de Mielina/deficiência , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/terapia , Animais , Sistemas CRISPR-Cas , Feminino , Edição de Genes , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora/genética , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Mutação Puntual , Testes de Função Respiratória , Análise de Sobrevida
4.
Cell Stem Cell ; 25(4): 531-541.e6, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585094

RESUMO

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.


Assuntos
Deferiprona/uso terapêutico , Células-Tronco Pluripotentes Induzidas/fisiologia , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Proteína Proteolipídica de Mielina/metabolismo , Oligodendroglia/fisiologia , Doença de Pelizaeus-Merzbacher/terapia , Animais , Diferenciação Celular , Células Cultivadas , Ferroptose , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/transplante , Peroxidação de Lipídeos , Camundongos , Camundongos Mutantes , Mutação/genética , Proteína Proteolipídica de Mielina/genética , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/transplante , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/patologia , Transplante de Células-Tronco , Reparo Gênico Alvo-Dirigido
5.
Stem Cell Reports ; 13(2): 254-261, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31378671

RESUMO

Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies.


Assuntos
Encéfalo/diagnóstico por imagem , Células-Tronco Neurais/transplante , Doença de Pelizaeus-Merzbacher/terapia , Encéfalo/fisiologia , Pré-Escolar , Seguimentos , Antígenos HLA/imunologia , Humanos , Lactente , Isoanticorpos/sangue , Imageamento por Ressonância Magnética , Masculino , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Doença de Pelizaeus-Merzbacher/imunologia , Doença de Pelizaeus-Merzbacher/patologia , Índice de Gravidade de Doença , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo , Resultado do Tratamento
6.
JCI Insight ; 4(10)2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31092737

RESUMO

Copy number increase or decrease of certain dosage-sensitive genes may cause genetic diseases with distinct phenotypes, conceptually termed genomic disorders. The most common cause of Pelizaeus-Merzbacher disease (PMD), an X-linked hypomyelinating leukodystrophy, is genomic duplication encompassing the entire proteolipid protein 1 (PLP1) gene. Although the exact molecular and cellular mechanisms underlying PLP1 duplication, which causes severe hypomyelination in the central nervous system, remain largely elusive, PLP1 overexpression is likely the fundamental cause of this devastating disease. Here, we investigated if adeno-associated virus-mediated (AAV-mediated) gene-specific suppression may serve as a potential cure for PMD by correcting quantitative aberrations in gene products. We developed an oligodendrocyte-specific Plp1 gene suppression therapy using artificial microRNA under the control of human CNP promoter in a self-complementary AAV (scAAV) platform. A single direct brain injection achieved widespread oligodendrocyte-specific Plp1 suppression in the white matter of WT mice. AAV treatment in Plp1-transgenic mice, a PLP1 duplication model, ameliorated cytoplasmic accumulation of Plp1, preserved mature oligodendrocytes from degradation, restored myelin structure and gene expression, and improved survival and neurological phenotypes. Together, our results provide evidence that AAV-mediated gene suppression therapy can serve as a potential cure for PMD resulting from PLP1 duplication and possibly for other genomic disorders.


Assuntos
MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Doença de Pelizaeus-Merzbacher/terapia , Animais , Sequência de Bases , Encéfalo/patologia , Morte Celular , Modelos Animais de Doenças , Dosagem de Genes , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Transgênicos , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Oligodendroglia , Doença de Pelizaeus-Merzbacher/genética , Fenótipo
7.
J Hum Genet ; 64(7): 665-671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004103

RESUMO

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.


Assuntos
Mutação da Fase de Leitura , Proteína Proteolipídica de Mielina/genética , Paraplegia/genética , Doença de Pelizaeus-Merzbacher/genética , Alelos , Linhagem Celular , Criança , Cromossomos Humanos X/genética , Cromossomos Humanos X/metabolismo , Decitabina/farmacologia , Feminino , Humanos , Doença de Pelizaeus-Merzbacher/patologia , Doença de Pelizaeus-Merzbacher/terapia , Piperazinas/farmacologia , Sequenciamento do Exoma
8.
Stem Cells ; 35(2): 311-315, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27882623

RESUMO

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutation in the proteolipid protein-1 (PLP1) gene, which encodes the proteolipid protein of myelinating oligodendroglia. PMD exhibits phenotypic variability that reflects its considerable genotypic heterogeneity, but all forms of the disease result in central hypomyelination, associated in most cases with early neurological dysfunction, progressive deterioration, and ultimately death. PMD may present as a connatal, classic and transitional forms, or as the less severe spastic paraplegia type 2 and PLP-null phenotypes. These disorders are most often associated with duplications of the PLP1 gene, but can also be caused by coding and noncoding point mutations as well as full or partial deletion of the gene. A number of genetically-distinct but phenotypically-similar disorders of hypomyelination exist which, like PMD, lack any effective therapy. Yet as relatively pure CNS hypomyelinating disorders, with limited involvement of the PNS and relatively little attendant neuronal pathology, PMD and similar hypomyelinating disorders are attractive therapeutic targets for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of research centers. Stem Cells 2017;35:311-315.


Assuntos
Doença de Pelizaeus-Merzbacher/terapia , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Modelos Animais de Doenças , Humanos , Mutação/genética , Bainha de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/patologia
9.
J Neurosci Res ; 94(12): 1572-1578, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27661457

RESUMO

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating leukodystrophy resulting from proteolipid protein 1 gene (PLP1) mutations leading to oligodendrocyte loss. While neuroinflammation has recently become a common feature and actor in neurodegenerative diseases, the involvement of inflammation in PMD physiopathology is still highly debated despite evidence for strong astrogliosis and microglial cell activation. Activation of the innate immune system, and more particularly, of microglia and astrocytes, is mostly associated with the deleterious role of neuroinflammation. However, in diseases such as multiple sclerosis, microglia appear beneficial for repair based on their role in myelin debris removal or recruitment and differentiation of oligodendrocyte progenitor cells. In this review, we will discuss recent published data in terms of their relevance to the role of microglia in PMD evolution, and of their impact on the improvement of therapeutic approaches combining immunomodulation and cell therapy to promote optimal recovery. © 2016 Wiley Periodicals, Inc.


Assuntos
Inflamação/patologia , Doença de Pelizaeus-Merzbacher/patologia , Humanos , Inflamação/terapia , Proteína Proteolipídica de Mielina/genética , Bainha de Mielina/patologia , Doença de Pelizaeus-Merzbacher/terapia
10.
Stem Cells ; 34(4): 984-96, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26676415

RESUMO

Pelizaeus-Merzbacher disease (PMD) results from an X-linked misexpression of proteolipid protein 1 (PLP1). This leukodystrophy causes severe hypomyelination with progressive inflammation, leading to neurological dysfunctions and shortened life expectancy. While no cure exists for PMD, experimental cell-based therapy in the dysmyelinated shiverer model suggested that human oligodendrocyte progenitor cells (hOPCs) or human neural precursor cells (hNPCs) are promising candidates to treat myelinopathies. However, the fate and restorative advantages of human NPCs/OPCs in a relevant model of PMD has not yet been addressed. Using a model of Plp1 overexpression, resulting in demyelination with progressive inflammation, we compared side-by-side the therapeutic benefits of intracerebrally grafted hNPCs and hOPCs. Our findings reveal equal integration of the donor cells within presumptive white matter tracks. While the onset of exogenous remyelination was earlier in hOPCs-grafted mice than in hNPC-grafted mice, extended lifespan occurred only in hNPCs-grafted animals. This improved survival was correlated with reduced neuroinflammation (microglial and astrocytosis loads) and microglia polarization toward M2-like phenotype followed by remyelination. Thus modulation of neuroinflammation combined with myelin restoration is crucial to prevent PMD pathology progression and ensure successful rescue of PMD mice. These findings should help to design novel therapeutic strategies combining immunomodulation and stem/progenitor cell-based therapy for disorders associating hypomyelination with inflammation as observed in PMD.


Assuntos
Imunidade Inata , Inflamação/terapia , Células-Tronco Neurais/transplante , Oligodendroglia/transplante , Doença de Pelizaeus-Merzbacher/terapia , Animais , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunomodulação , Inflamação/imunologia , Inflamação/patologia , Camundongos , Microglia/imunologia , Microglia/patologia , Proteína Proteolipídica de Mielina/biossíntese , Bainha de Mielina/metabolismo , Células-Tronco Neurais/imunologia , Oligodendroglia/imunologia , Doença de Pelizaeus-Merzbacher/imunologia , Doença de Pelizaeus-Merzbacher/patologia , Regeneração
11.
Pediatrics ; 134(5): e1451-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25287453

RESUMO

Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/terapia , Pré-Escolar , Seguimentos , Humanos , Lactente , Masculino , Resultado do Tratamento
12.
Semin Neurol ; 34(3): 312-20, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25192509

RESUMO

Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have a reported incidence of 1 in 7500 live births, but fewer than half of patients receive a specific diagnosis. In this review, the authors discuss types of leukodystrophies: their prevalence, clinical presentation, symptoms, and diagnosis, as well as current and future treatments. Diagnosis is based on a combination of history, exam, radiological, and laboratory findings, including genetic testing. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Their high prevalence, combined with rapid advances in imaging, genetics, and potential treatments, makes an understanding of the leukodystrophies necessary for care providers in genetics and neurology.


Assuntos
Encefalopatias/genética , Predisposição Genética para Doença , Doenças por Armazenamento dos Lisossomos/genética , Bainha de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/genética , Animais , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Humanos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/terapia , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/terapia , Prevalência
13.
Stem Cell Reports ; 2(5): 648-61, 2014 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-24936452

RESUMO

Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.


Assuntos
Estresse do Retículo Endoplasmático , Células-Tronco Pluripotentes Induzidas/citologia , Proteína Proteolipídica de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , Adolescente , Adulto , Animais , Encéfalo/diagnóstico por imagem , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação de Sentido Incorreto , Proteína Proteolipídica de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/transplante , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/terapia , Radiografia , Teratoma/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto Jovem
14.
Nucleic Acid Ther ; 24(1): 69-86, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24506781

RESUMO

Alternative splicing is an important regulator of the transcriptome. However, mutations may cause alteration of splicing patterns, which in turn leads to disease. During the past 10 years, exon skipping has been looked upon as a powerful tool for correction of missplicing in disease and progress has been made towards clinical trials. In this review, we discuss the use of antisense oligonucleotides to correct splicing defects through exon skipping, with a special focus on diseases affecting the nervous system, and the latest stage achieved in its progress.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/terapia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Reparo Gênico Alvo-Dirigido/métodos , Animais , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/terapia , Barreira Hematoencefálica , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/terapia , Cistos/genética , Cistos/terapia , Sistemas de Liberação de Medicamentos , Éxons , Demência Frontotemporal/genética , Demência Frontotemporal/terapia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Mutação , Neurofibromatoses/genética , Neurofibromatoses/terapia , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/terapia , Oligonucleotídeos Antissenso/química , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/terapia , Fosfotransferases (Fosfomutases)/deficiência , Fosfotransferases (Fosfomutases)/genética , Splicing de RNA
18.
Sci Transl Med ; 4(155): 155ra137, 2012 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-23052294

RESUMO

Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Bainha de Mielina/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Doença de Pelizaeus-Merzbacher/terapia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos
19.
Semin Neurol ; 32(1): 62-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22422208

RESUMO

The purpose of this article is to present contemporary information on the clinical and molecular diagnosis and the treatment of Pelizaeus-Merzbacher's disease (PMD) and related leukodystrophies. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. A diffuse pattern of hypomyelination is seen on magnetic resonance imaging (MRI) of PMD/SPG2 patients. A similar constellation of signs and pattern of hypomyelination lead to the autosomal recessive disease called Pelizaeus-Merzbacher-like disease 1 (PMLD1) and the less-severe spastic paraplegia 44 (SPG44), caused by mutations of the gap junction protein, gamma-2 gene (GJC2), formerly known as the gap junction protein, α-12 gene (GJA12). Magnetic resonance spectroscopy (MRS) and brainstem auditory evoked potentials (BAEP) may assist with differential clinical diagnosis of PMD and PMLD1. Supportive therapy for patients with PMD/SPG2 and PMLD1/SPG44 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.


Assuntos
Doenças Desmielinizantes/genética , Paraplegia/genética , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/genética , Doenças Desmielinizantes/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação/genética , Paraplegia/diagnóstico , Doença de Pelizaeus-Merzbacher/terapia
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