Oligodendroglial Progenitor Cell Therapy Limits Central Neurological Deficits in Mice with Metachromatic Leukodystrophy

Givogri, Maria I.; Galbiati, Francesca; Fasano, Stefania; Amadio, Stefano; Perani, Laura; Superchi, Daniela; Morana, Pablo; Carro, Ubaldo Del; Marchesini, Sergio; Brambilla, Riccardo; Wrabetz, Lawrence; Bongarzone, Ernesto R.

doi:10.1523/jneurosci.4366-05.2006

Cited by 60 publications

(52 citation statements)

References 69 publications

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“…A recent study has provided evidence that grafted primary oligodendrocyte progenitors can reduce sulfatide storage in the brain of MLD mutant mice. 20 However, when extrapolated to clinical applications, the application of primary cells is limited by the shortage of donor tissue, batch-to-batch variations typically encountered in primary cell preparations and restricted expandability.…”

Section: Discussionmentioning

confidence: 99%

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy

et al. 2006

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Pluripotency, virtually unlimited self-renewal and amenability to genetic modification make embryonic stem (ES) cells an attractive donor source for cell-mediated gene therapy. In this proof of concept study, we explore whether glial precursors derived from murine ES cells (ESGPs) and engineered to overexpress human arylsulfatase A (hASA) can cross-correct the metabolic defect in an animal model of metachromatic leukodystrophy (MLD). Transfected ES cells showed an up to 30-fold increase in ASA activity. Following in vitro differentiation, high expression of ASA was found in all stages of neural and glial differentiation. hASA-overexpressing ESGPs maintained their ability to differentiate into astrocytes and oligodendrocytes in vitro and in vivo. After transplantation into the brain of neonatal ASA-deficient mice, hASA-overexpressing ESGPs were found to incorporate into a variety of host brain regions. Four weeks after engraftment, immunofluorescence analyses with an antibody to sulfatide revealed a 46.774.0% reduction of immunoreactive sulfatide deposits in the vicinity of the hASA-positive engrafted cells, thereby significantly extending the rate of sulfatide reduction achieved by the endogenous ASA activity of non-hASA-transfected control cells (21.175.8%). These findings provide first in vivo evidence that ES cells may serve as a potential donor source for cell-mediated enzyme delivery in storage disorders such as MLD.

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Section: Discussionmentioning

confidence: 99%

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy

et al. 2006

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“…Mesenchymal and hematopoietic stem cell grafts have proven unable to correct the CNS manifestations of this disorder (Koc et al 2002). In contrast, experimental models of MLD have responded well to OPC grafts (Givogri et al 2006), suggesting that the broader dispersal competence and greater histiotypic appropriateness of orthotopically engrafted OPCs might provide significant therapeutic advantages relative to nonneural phenotypes. Similarly, although asymptomatic Krabbe patients transplanted with umbilical cord stem cells manifested slower disease progression than untreated controls, the benefits of transplantation to children engrafted after symptom onset seemed minimal (Escolar et al 2005).…”

Section: Neonatal Delivery Of Opcs For Enzymatic Reconstitution and Mmentioning

confidence: 99%

Glia Disease and Repair—Remyelination

Franklin

Goldman

2015

Cold Spring Harb Perspect Biol

190

168

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The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, although this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granular neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet, remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this review, we will review the biology of remyelination, including the cells and signals involved; describe when remyelination occurs and when and why it fails and the consequences of its failure; and discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain. IDENTIFYING REMYELINATIONR emyelination is the process in which new myelin sheaths are restored to axons that have lost their myelin sheaths as a result of primary demyelination. Primary demyelination is the term used to describe the loss of myelin from an otherwise intact axon and should be distinguished from myelin loss secondary to axonal loss-a process called Wallerian degeneration or, misleadingly, secondary demyelination. Remyelination is sometimes referred to as myelin repair. However, this term suggests a damaged but otherwise intact myelin internode being "patched up," a process for which there is no evidence and which does not emphasize the truly regenerative nature of remyelination, in which the prelesion cytoarchitecture is substantially restored. Remyelinated tissue very closely resembles normally myelinated tissue but differs in one important aspect-the newly generated myelin sheaths are typically shorter and thinner than the original myelin sheaths. When myelin is initially formed in the peri-and postnatal period, there is a striking correlation between axon diameter and myelin sheath thickness and length, which is less apparent in remyelination. Instead, myelin sheath thickness and

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“…Accordingly, transplantation of GLD HSC in normal congenic recipients allowed normal lymphopoiesis. Although it remains to be determined whether enzyme crosscorrection by host cells mitigate the GALC deficiency of donor Twitcher cells (Neufeld and Fratantoni, 1970;Kondo et al, 2005;Givogri et al, 2006), the finding that GLD recipients of normal congenic HSC became progressively lymphopenic, is rather indicative of the existence of epigenetic factors contributing to thymic involution in GLD. Although we do not propose lymphoid atrophy as causative for GLD, we believe it is an additive pathological factor contributing to a very complex and rapidly degenerating phenotype.…”

Section: Cell Autonomous and Epigenetic Mechanisms Contributing To Immentioning

confidence: 99%

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

Galbiati¹,

Basso²,

Cantuti³

et al. 2007

J. Neurosci.

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Lysosomal ␤-galactosylceramidase deficiency results in demyelination and inflammation in the nervous system causing the neurological Krabbe disease. In the Twitcher mouse model of this disease, we found that neurological symptoms parallel progressive and severe lymphopenia. Although lymphopoiesis is normal before disease onset, primary and secondary lymphoid organs progressively degenerate afterward. This occurs despite preserved erythropoiesis and leads to severe peripheral lymphopenia caused by reduced numbers of T cell precursors and mature lymphocytes. Hematopoietic cell replacement experiments support the existence of an epigenetic factor in mutant mice reconcilable with a progressive loss of autonomic axons that hampers thymic functionality. We propose that degeneration of autonomic nerves leads to the irreversible thymic atrophy and loss of immune-competence. Our study describes a new aspect of Krabbe disease, placing patients at risk of immune-related pathologies, and identifies a novel target for therapeutic interventions.

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Oligodendroglial Progenitor Cell Therapy Limits Central Neurological Deficits in Mice with Metachromatic Leukodystrophy

Cited by 60 publications

References 69 publications

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy

Glia Disease and Repair—Remyelination

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

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