Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice

Sakurai, Katsunobu; Iizuka, Sayoko; Js, Shen; Xl, Meng; Mori, Taisuke; Umezawa, Akihiro; Ohashi, Toya; Eto, Yoshikatsu

doi:10.1038/sj.gt.3302338

Cited by 37 publications

(16 citation statements)

References 27 publications

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“…In fact, transplantation of b-glucuronidase-expressing neural progenitor cells into the brain of mucopolysaccharidosis mice led to a reduction and in the case of transplantation of b-glucuronidase overexpressing bone marrow stromal cells to an almost complete normalization of glycosaminoglycan storage in the treated animals. 22,33 These diverse results indicate that the therapeutic efficacy of cell-based enzyme delivery cannot be generalized for all lysosomal storage disorders but depends critically on disease-specific parameters such as secretion rates, diffusion distance and interaction with the storage compound.…”

Section: Different Lysosomal Storage Diseases May Exhibit Different Amentioning

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: Different Lysosomal Storage Diseases May Exhibit Different Amentioning

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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“…Progress along those lines has been made in rodent models of neurodegenerative disorders, such as Parkinson's disease [13,60], and lysosomal storage disorders, including Tay-Sachs disease [53], Niemann-Pick disease types A and B [61,62], and mucopolysaccharidosis Type VII [63].…”

Section: Mesenchymal Stem Cells As Platforms For Recombinant Protein mentioning

confidence: 99%

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases

Reiser

Zhang

Hemenway

et al. 2005

Expert Opinion on Biological Therapy

166

114

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The intriguing biology of stem cells and their vast clinical potential is emerging rapidly for gene therapy. Bone marrow stem cells, including the pluripotent haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and possibly the multipotent adherent progenitor cells (MAPCs), are being considered as potential targets for cell and gene therapy-based approaches against a variety of different diseases. The MSCs from bone marrow are a promising target population as they are capable of differentiating along multiple lineagesn and, at least in vitro, have significant expansion capability. The apparently high self-renewal potential makes them strong candidates for delivering genes and restoring organ systems function. However, the high proliferative potential of MSCs, now presumed to be self-renewal, may be more apparent than real. Although expanded MSCs have great proliferation and differentiation potential in vitro, there are limitations with the biology of these cells in vivo. So far, expanded MSCs have failed to induce durable therapeutic effects expected from a true self-renewing stem cell population. The loss of in vivo self-renewal may be due to the extensive expansion of MSCs in existing in vitro expansion systems, suggesting that the original stem cell population and/or properties may no longer exist. Rather, the expanded population may indeed be heterogeneous and represents several generations of different types of mesenchymal cell progeny that have retained a limited proliferation potential and responsiveness for terminal differentiation and maturation along mesenchymal and non-mesenchymal lineages. Novel technology that allows MSCs to maintain their stem cell function in vivo is critical for distinguishing the elusive stem cell from its progenitor cell populations. The ultimate dream is to use MSCs in various forms of cellular therapies, as well as genetic tools that can be used to better understand the mechanisms leading to repair and regeneration of damaged or diseased tissues and organs.

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“…Various cell sources have been tested either alone as intracranial injections [Snyder et al 1992, Buchet et al 2002, Meng et al 2003, Newman et al 2004, Sakurai et al 2004, or as adjunct therapies to HSCT [Jin et al 2003]. Although human mesenchymal stem cells (MSCs) produce several lysosomal enzymes [Koc et al 1999] no other presently identified source of neural stem cells produces enough endogenous lysosomal enzymes, and must overexpress the proteins from an integrating vector to provide a cross corrective function [Lacorazza et al 1996, Buchet et al 2002, Meng et al 2003, Shihabuddin et al 2004, Sakurai et al 2004].…”

Section: Neural and Mesenchymal Stem Cellsmentioning

confidence: 99%

Cell and Gene-Based Therapies for the Lysosomal Storage Diseases

Hodges¹,

Cheng²

2006

CGT

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Lysosomal storage disorders (LSD) are a group of approximately 40 genetic diseases that are caused by the deficiency of one or more lysosomal enzymes. The incidence of LSD is estimated to be approximately 1 in 7500 live births, which makes this one of the more prevalent groups of genetic diseases in humans. The loss in enzymatic activity leads to the accumulation of undegraded substrates within lysosomes, resulting in distension of the organelle and subsequent cellular malfunction. Although palliative treatments such as enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) have been shown to be effective for some of the LSD such as Gaucher, Fabry and MPS I, they are not available as yet, or ineffective, for a large number of other LSD patients. To fulfill this unmet medical need, gene therapy is being considered as an alternate or adjunctive therapy for this group of disorders. A goal of gene therapy for LSD is to introduce a normal copy of the DNA for the lysosomal enzyme into a depot organ such as the liver or muscle with the intent that this will lead to the sustained production and re-constitution of therapeutic levels of the enzyme in the affected tissues. Here, we review the utility of various gene therapy strategies under consideration for the treatment of the LSD, including viral and non-viral gene transfer approaches, as well as stem cell transplantation.

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Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice

Cited by 37 publications

References 27 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

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases

Cell and Gene-Based Therapies for the Lysosomal Storage Diseases

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