Effect of neonatal administration of a retroviral vector expressing α-l-iduronidase upon lysosomal storage in brain and other organs in mucopolysaccharidosis I mice

Chung, Sarah; Ma, Xiucui; Liu, Yuli; Lee, David; Tittiger, Mindy; Ponder, Katherine P.

doi:10.1016/j.ymgme.2006.08.001

Cited by 47 publications

(42 citation statements)

References 32 publications

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“…Even at concentrations equal to C4-S, the presence of DS and HS strongly inhibits the collagenolytic activity of cathepsin K. In MPS tissues, the concentration of GAGs can reach 7 to 20 times the concentration normally found in liver and bone. 24,25 Therefore, cathepsin K expressed by osteoclasts would likely have a reduced ability to degrade the cartilage during endochondral ossification in such an environment. Moreover, general bone remodeling might also be affected, as shown by the decreased ability of recombinant human cathepsin K to degrade MPS I bone powder, demonstrating the importance of regulated GAG expression in bone.…”

Section: Discussionmentioning

confidence: 99%

“…The quantities of accumulated GAGs in Idua Ϫ/Ϫ tissues have been determined in tissues such as liver and lung, but not for bone or joint. In liver, lungs, and ovaries, the concentration of GAGs can reach up to 20 times the normal physiological concentration 24,25 ; therefore in our degradation assay, we added the equivalent concentration to mimic in vivo conditions. The extent of degradation was visualized by Coomassie staining of type II collagen cleavage fragments after gel electrophoresis.…”

Section: Type II Collagen Degradation By Cathepsin K In Presence Of Gagsmentioning

confidence: 99%

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Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

Wilson

Hashamiyan

Clarke

et al. 2009

The American Journal of Pathology

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Mucopolysaccharidoses are a group of lysosomal storage diseases characterized by the build-up of glycosaminoglycans (GAGs) and severe skeletal abnormalities. As GAGs can regulate the collagenolytic activity of the major osteoclastic protease cathepsin K, we investigated the presence and activity of cathepsin K and its co-localization with GAGs in mucopolysaccharidosis (MPS) type I bone. The most dramatic difference between MPS I and wild-type mice was an increase in the amount of cartilage in the growth plates in MPS I bones. Though the number of cathepsin K-expressing osteoclasts was increased in MPS I mice, these mice revealed a significant reduction in cathepsin K-mediated cartilage degradation. As excess heparan and dermatan sulfates inhibit type II collagen degradation by cathepsin K and the spatial overlap between cathepsin K and heparan sulfate strongly increased in MPS I mice, the build up of subepiphyseal cartilage is speculated to be a direct consequence of cathepsin K inhibition by MPS I-associated GAGs. Moreover, isolated MPS I and Ctsk ؊/؊ osteoclasts displayed fewer actin rings and formed fewer resorption pits on dentine disks, as compared with wild-type cells. These results suggest that the accumulation of GAGs in murine MPS I bone has an inhibitory effect on cathepsin K activity, resulting in impaired osteoclast activity and decreased cartilage resorption, which may contribute to the bone pathology seen in MPS diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Type II Collagen Degradation By Cathepsin K In Presence Of Gagsmentioning

confidence: 99%

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

Wilson

Hashamiyan

Clarke

et al. 2009

The American Journal of Pathology

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“…This premise was initially based on observations that intravenous injection of very high levels of recombinant lysosomal enzymes can result in partial clearance of lysosomal storage in the CNS of select young animal models of the diseases (75)(76)(77). The viability of early systemic intervention with high levels of enzyme to treat the CNS was further supported by systemic gene therapy studies (which effected continuous hepatic expression of the enzymes) in murine models of MPS I, MPS III, and MPS VII (78)(79)(80). Evidence of a reduction of the corresponding substrates in the CNS of these animals was demonstrated.…”

Section: Prospects Of Systemically Delivered Aav Vectors To Address Tmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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“…Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in MPS I animal models upon neonatal treatment. [6][7][8][9] However, residual disease still affected the nervous and skeletal tissues and the aorta of mice treated with this approach in adulthood. 10,11 This limited efficacy could be due to insufficient enzyme delivery via the bloodstream to tissues, such as the brain, protected by physiologic barriers or poorly vascularized, such as the skeleton, and/or to immune-mediated clearance of the liver-secreted enzyme.…”

Section: Introductionmentioning

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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Effect of neonatal administration of a retroviral vector expressing α-l-iduronidase upon lysosomal storage in brain and other organs in mucopolysaccharidosis I mice

Cited by 47 publications

References 32 publications

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

Gene therapy for the neurological manifestations in lysosomal storage disorders

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

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