Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells

Biffi, Alessandra; Palma, Michele De; Quattrini, Angelo; Carro, Ubaldo Del; Amadio, Stefano; Visigalli, Ilaria; Sessa, Maria; Fasano, Stefania; Brambilla, Riccardo; Marchesini, Sergio; Bordignon, Claudio; Naldini, Luigi

doi:10.1172/jci19205

Cited by 114 publications

(95 citation statements)

References 49 publications

(18 reference statements)

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“…ASA-deficient mice have been extensively used to evaluate therapeutical approaches for MLD, e.g., adenoassociated viral-and lentiviral-mediated gene therapy [74][75][76], gene therapy using hematopoietic stem cells [77][78][79][80], enzyme replacement therapy [81], and cell-based therapies using oligodendrocyte progenitors [82] or embryonic stem cell-derived oligodendrocytes [83]. These studies have been described in several recent reviews [84][85][86][87] and will, therefore, not be discussed in this paper.…”

Section: Pathology Of Sulfatide Storagementioning

confidence: 99%

The Role and Metabolism of Sulfatide in the Nervous System

2008

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3-O-sulfogalactosylceramide or sulfatide is a major component of the myelin sheath in the central and peripheral nervous system. The examination of mice deficient in the sulfatide-synthesizing enzyme, cerebroside sulfotransferase, provided new insight into the role of sulfatide in the differentiation of myelinating cells, formation of the paranodal junction, and myelin maintenance. Although in general regarded as a marker for oligodendrocytes and Schwann cells, sulfatide is also present in astrocytes and neurons. The relatively low amount of sulfatide in neurons can dramatically increase in the absence of the sulfatide-degrading enzyme, arylsulfatase A, as in metachromatic leukodystrophy. Recent advance in the understanding of this disease comes from studies on new transgenic mouse models. Significant changes in sulfatide levels have also been observed more recently in Alzheimer's disease and other diseases, suggesting that sulfatide might be involved in the pathogenesis of these diseases as well. This review summarizes recent studies on the physiological and pathophysiological role of sulfatide using transgenic mice deficient in its synthesis or degradation.

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Section: Pathology Of Sulfatide Storagementioning

confidence: 99%

The Role and Metabolism of Sulfatide in the Nervous System

2008

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“…Therefore, a novel therapeutic approach to retinal diseases includes the use of BM-derived microglia as vehicles for gene delivery and therapeutic proteins [13,17,39,131]. Furthermore, it is possible for them to transfer neurotrophins or other beneficial substances into the injured retina [132].…”

Section: Bm-derived Cells As Vehicles Of Gene Delivery and Therapeutimentioning

confidence: 99%

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

et al. 2016

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Microglia are immune cells in the central nervous system (CNS) that originate from the yolk sac in an embryo. The renewal of the microglia pool in the adult eye consists of two components. In addition to the self-proliferation of resident cells, microglia in the CNS also derive from the bone marrow (BM). BM-derived cells pass through the blood-brain barrier (BBB) or blood-retina barrier (BRB) and differentiate into microglia under specific conditions which involves a complex mechanism. Recent studies have widely investigated the role of resident microglia and BM-derived microglia in the retinal degenerative disease. Both two cell types play dual roles and share many similar functions. However, resident microglia tend to polarize to the M1 phenotype which is pro-inflammatory and neurotoxic, whereas BM-derived microglia mainly polarize to the neuroprotective M2 phenotype in retinal degeneration. The molecular mechanism that underlines the invasion of peripheral cells has led to extensive discussions. In addition to the BBB and BRB disruption, many signaling pathways are involved in this process. Based on these studies, we discuss the roles of these two types of microglia in retinal degeneration disease and the potential clinical application of BM-derived microglia, which may benefit future therapies.

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“…The intravenous injection of such AAV2 vectors expressing therapeutic protein of the MPS-VII (deficient enzyme = β-glucoronidase) and late infantile neuronal ceroid lipofuscinosis (deficient enzyme = tripeptidyl peptidase I) markedly increased the affinity of the vectors to the brain and reversed storage material in the brain of the respective mice models (Chen et al 2009). Ex vivo gene transfer into hematopoietic cells and, subsequently, into a model of metachromatic leukodystrophy or into multipotent neural cell lines of the mouse model for Tay-Sachs disease, using a retroviral vector, also show some promise (Biffi et al 2004;Lacorazza et al 1996). The only published treatment trial of CNS gene therapy in an LSD is a phase I study looking mostly at safety of late infantile ceroid lipofuscinosis using direct injection of AAV2 coding containing the CLN2 vector (that codes for the deficient enzyme in this disease, tripeptidyl-peptidase I, into the brain of ten children with this disease (Worgall et al 2008).…”

Section: Gene Therapymentioning

confidence: 99%

Therapeutic approaches for neuronopathic lysosomal storage disorders

Schiffmann

2010

J of Inher Metab Disea

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Therapy of the central nervous system (CNS) manifestations of lysosomal storage diseases (LSDs) has remained a major challenge because of its inability to deliver therapeutic agents efficiently across the intact blood-brain barrier. Non-specific therapies such as hematopoietic stem cell transplantation have been useful in globoid cell leukodystrophy (Krabbe disease) and in some mucopolysaccharidoses. Anti-inflammatory agents also show promise as adjuvant therapy. High doses of replacement therapy with native or modified enzyme show renewed promise for correction of CNS cells. Alternatively, small molecules can enter the brain relatively easily and promote reduction of accumulated substrate or function as pharmacological chaperones to enhance the level of the deficient enzyme. Gene therapy is still being developed and tested in patients. It is therefore likely that, thanks to a better understanding of disease mechanism, a variety of therapeutic approaches, used alone or in combination, will be useful to treat the devastating neurological complications of LSDs.

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Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells

Cited by 114 publications

References 49 publications

The Role and Metabolism of Sulfatide in the Nervous System

The Role and Metabolism of Sulfatide in the Nervous System

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

Therapeutic approaches for neuronopathic lysosomal storage disorders

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