Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy

Lee, Wing C.; Courtenay, Andrew; Troendle, Frederick J.; Stallings-Mann, Melody; Dickey, Chad A.; DeLucia, Michael W.; Dickson, Dennis W.; Eckman, Christopher B.

doi:10.1096/fj.05-3826fje

Cited by 79 publications

(83 citation statements)

References 39 publications

(56 reference statements)

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“…[32][33][34][35][36] These results, which, in some cases, are not associated to an overt benefit in terms of neurologic symptom alleviation, are far from being understood. Anyhow, the efficacy of HSC gene therapy could also be related to some IDUA protein being secreted by the transduced hematopoietic cells into the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Visigalli

Delai

Politi

et al. 2010

Blood

163

157

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Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment. [6][7][8][9] However, residu...

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Section: Discussionmentioning

confidence: 99%

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Visigalli

Delai

Politi

et al. 2010

Blood

163

157

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“…However, over the past few years, researchers have investigated high-dose ERT in animal models of a number of LSD, including MPS VII , Krabbe disease (Lee et al, 2005), metachromatic leukodystrophy (MLD; Matzner et al, 2009) and MPS IIIA (Rozaklis et al, 2011). With the exception of the latter study in MPS IIIA mice, these reports demonstrate that high dose ERT can mediate reductions in neuropathology and, in some cases, improve neurological function.…”

Section: Enzyme Replacement Therapymentioning

confidence: 99%

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

Arfi¹,

Richard²,

Scherman³

2012

Latest Findings in Intellectual and Developmental Disabilities Research

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“…Therefore, replacing GALC in oligodendrocytes and Schwann cells, either endogenously or exogenously, is critical as a therapeutic approach in Krabbe disease. For example, enzyme replacement by intravenous administration of synthetic GALC has moderately improved the clinicopathology of twi mice [94]. However, the effect is limited because the GALC protein does not cross the blood brain barrier to reach the CNS.…”

Section: Transplantation Of Cells Into the Twi Mousementioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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The leukodystrophies are rare and serious genetic disorders of the central nervous system that primarily affect children who frequently die early in life or have significantly delayed motor and mental milestones that result in long-term disability. Although with some of these disorders, early intervention with bone marrow or cord blood transplantation has been proven useful, it has not yet been determined that such therapies promote myelin repair of the central nervous system. Research on experimental therapies aimed at myelin repair is aided by the ability to test cell replacement strategies in genetic models in which the mutations and neuropathology match the human disorder. Thus, models exist of Pelizaeus-Merzbacher disease and the lysosomal storage disorder, Krabbe disease, which reflect the clinical and pathological course of the human disorders. Collectively, animals with mutations in myelin genes are called the myelin mutants, and they include rodent models such as the shiverer mouse that have been extensively used to study myelination by exogenous cell transplantation. These studies have encompassed many permutations of the age of the recipient, type of transplanted cell, site of engraftment, and so forth, and they offer hope that the scaling up of myelin produced by transplanted cells will have clinical significance in treating patients. Here we review these models and discuss their relative importance and use in such translational approaches. We discuss how grafts are identified and functional outcomes are measured. Finally, we briefly discuss the cells that have been successfully transplanted, which may be used in future clinical trials.

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Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy

Cited by 79 publications

References 39 publications

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

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