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Emil D. Kakkis - One of the best experts on this subject based on the ideXlab platform.
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immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis i
Journal of Clinical Investigation, 2008Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Maryn Peinovich, Thomas Lester, Steven Q Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Emil D. KakkisAbstract:Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-Iduronidase successfully reduces lysosomal storage in canines and humans with Iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-Iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to Iduronidase could improve the effectiveness of recombinant Iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to Iduronidase or left nontolerant. All canines received i.v. recombinant Iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed Iduronidase-specific antibodies that proportionally reduced in vitro Iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to Iduronidase improved the efficacy of enzyme replacement therapy with recombinant Iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.
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intrathecal enzyme replacement therapy successful treatment of brain disease via the cerebrospinal fluid
Molecular Genetics and Metabolism, 2007Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Carole Vogler, Beth Levy, Maryn Peinovich, Stephen Hanson, Emil D. KakkisAbstract:Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human Iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal Iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
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intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of mps i
Molecular Genetics and Metabolism, 2004Co-Authors: Emil D. Kakkis, Patricia I Dickson, Michael F Mcentee, Carole Vogler, Beth Levy, Stephen Hanson, Pavel V Belichenko, William C Mobley, Merry PassageAbstract:Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-Iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of Iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
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successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis i
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Emil D. Kakkis, Maryn Peinovich, Thomas Lester, R Yang, C Tanaka, Vikram Anand, Jeffrey F Lemontt, Merry PassageAbstract:Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme α-l-Iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human α-l-Iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because α-l-Iduronidase and α-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated α-l-Iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.
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immune tolerance after long term enzyme replacement therapy among patients who have mucopolysaccharidosis i
The Lancet, 2003Co-Authors: Revecca Kakavanos, Christopher T Turner, Emil D. Kakkis, Doug A. BrooksAbstract:Summary Background Enzyme-replacement therapy has been assessed as a treatment for patients who have mucopolysaccharidosis I (α-L-Iduronidase deficiency). We aimed to investigate the humoral immune response to recombinant human α-L-Iduronidase among these patients. Methods We characterised the antibody titres and specific linear sequence epitope reactivity of serum antibodies to α-L-Iduronidase for ten patients with mucopolysaccharidosis I, at the start of treatment and after 6, 12, 26, 52, and 104 weeks. We compared the values for patients' samples with those for samples from normal human controls. Findings Before enzyme-replacement therapy, all patients had low serum antibody titres to recombinant human α-L-Iduronidase that were within the control range. Five of the ten patients produced higher-than-normal titres of antibody to the replacement protein during the treatment course (serum antibody titres 130 000–500 000 and high-affinity epitope reactivity). However, by week 26, antibody reactivity was reduced, and by week 104 all patients had low antibody titres and only low-affinity epitope reactivity. Patients who had mucopolysaccharidosis I with antibody titres within the normal range at 6–12 weeks did not subsequently develop immune responses. Interpretation After 2 years of treatment, patients who initially had an immune reaction developed immune tolerance to α-L-Iduronidase. This finding has positive implications for long-term enzyme-replacement therapy in patients who have mucopolysaccharidosis I.
Merry Passage - One of the best experts on this subject based on the ideXlab platform.
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specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis i
Molecular Genetics and Metabolism, 2012Co-Authors: Patricia I Dickson, Merry Passage, Moin Vera, Matthew N Ellinwood, Jillian R Brown, Robert G Witt, Brett E CrawfordAbstract:Abstract Intrathecal enzyme replacement therapy is an experimental option to treat central nervous system disease due to lysosomal storage. Previous work shows that MPS I dogs receiving enzyme replacement with recombinant human alpha- l -Iduronidase into the cisterna magna showed normal brain glycosaminoglycan (GAG) storage after three or four doses. We analyzed MPS I dogs that received intrathecal enzyme in a previous study using an assay that detects only pathologic GAG (pGAG). To quantify pGAG in MPS I, the assay measures only those GAG which display terminal iduronic acid residues on their non-reducing ends. Mean cortical brain pGAG in six untreated MPS I dogs was 60.9 ± 5.93 pmol/mg wet weight, and was 3.83 ± 2.64 in eight normal or unaffected carrier animals (p
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replacing the enzyme α l Iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type i
Science Translational Medicine, 2010Co-Authors: Ashley Dierenfeld, Merry Passage, Michael F Mcentee, Carole Vogler, Charles H Vite, Agnes Chen, S Shah, J K Jens, Elizabeth M Snella, Karen L KlineAbstract:Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-Iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-Iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-Iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.
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immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis i
Journal of Clinical Investigation, 2008Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Maryn Peinovich, Thomas Lester, Steven Q Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Emil D. KakkisAbstract:Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-Iduronidase successfully reduces lysosomal storage in canines and humans with Iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-Iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to Iduronidase could improve the effectiveness of recombinant Iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to Iduronidase or left nontolerant. All canines received i.v. recombinant Iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed Iduronidase-specific antibodies that proportionally reduced in vitro Iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to Iduronidase improved the efficacy of enzyme replacement therapy with recombinant Iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.
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intrathecal enzyme replacement therapy successful treatment of brain disease via the cerebrospinal fluid
Molecular Genetics and Metabolism, 2007Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Carole Vogler, Beth Levy, Maryn Peinovich, Stephen Hanson, Emil D. KakkisAbstract:Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human Iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal Iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
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intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of mps i
Molecular Genetics and Metabolism, 2004Co-Authors: Emil D. Kakkis, Patricia I Dickson, Michael F Mcentee, Carole Vogler, Beth Levy, Stephen Hanson, Pavel V Belichenko, William C Mobley, Merry PassageAbstract:Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-Iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of Iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
Chester B Whitley - One of the best experts on this subject based on the ideXlab platform.
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Standardization of α-L-Iduronidase enzyme assay with Michaelis-Menten kinetics.
Molecular genetics and metabolism, 2013Co-Authors: Tyler Herzog, Carrie M. Wilmot, Chester B WhitleyAbstract:Abstract The lack of methodological uniformity in enzyme assays has been a long-standing difficulty, a problem for bench researchers, for the interpretation of clinical diagnostic tests, and an issue for investigational drug review. Illustrative of the problem, α-L-Iduronidase enzyme catalytic activity is frequently measured with the substrate 4-methylumbelliferyl-α-L-iduronide (4MU-iduronide); however, final substrate concentrations used in different assays vary greatly, ranging from 25μM to 1425μM ( K m ≈180μM) making it difficult to compare results between laboratories. In this study, α-L-Iduronidase was assayed with 15 different substrate concentrations. The resulting activity levels from the same specimens varied greatly with different substrate concentrations but, as a group, obeyed the expectations of Michaelis–Menten kinetics. Therefore, for the sake of improved comparability, it is proposed that α-L-Iduronidase enzyme assays should be conducted either (1) under substrate saturating conditions; or (2) when concentrations are significantly below substrate saturation, with results standardized by arithmetic adjustment that considers Michaelis–Menten kinetics. The approach can be generalized to many other enzyme assays.
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direct gene transfer to the cns prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type i
Neurobiology of Disease, 2011Co-Authors: Daniel A Wolf, Chester B Whitley, Andrew W Lenander, Lalitha R Belur, Pankaj Gupta, Scott R. McivorAbstract:Abstract The mucopolysaccharidoses (MPSs) are a group of 11 storage diseases caused by disruptions in glycosaminoglycan (GAG) catabolism, leading to their accumulation in lysosomes. Resultant multisystemic disease is manifested by growth delay, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, and, in severe MPS I, II, III, and VII, progressive neurocognitive decline. Some MPSs are treated by allogeneic hematopoietic stem cell transplantation (HSCT) and/or recombinant enzyme replacement therapy (ERT), but effectiveness is limited by central nervous system (CNS) access across the blood-brain barrier. To provide a high level of gene product to the CNS, we tested neonatal intracerebroventricular (ICV) infusion of an adeno-associated virus (AAV) serotype 8 vector transducing the human α- l -Iduronidase gene in MPS I mice. Supranormal levels of Iduronidase activity in the brain (including 40× normal levels in the hippocampus) were associated with transduction of neurons in motor and limbic areas identifiable by immunofluorescence staining. The treatment prevented accumulation of GAG and GM3 ganglioside storage materials and emergence of neurocognitive dysfunction in a modified Morris water maze test. The results suggest the potential of improved outcome for MPSs and other neurological diseases when a high level of gene expression can be achieved by direct, early administration of vector to the CNS.
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combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for hurler syndrome
Bone Marrow Transplantation, 2008Co-Authors: Jakub Tolar, Chester B Whitley, Satkiran S Grewal, Kendra Bjoraker, Elsa Shapiro, Lawrence Charnas, Paul J OrchardAbstract:Hurler syndrome (mucopolysaccharidosis type I, MPS IH) is characterized by a deficiency of α-L-Iduronidase resulting in progressive multiorgan dysfunction. We sought to determine whether enzyme replacement therapy (ERT) with Iduronidase in the peritransplant period affects outcome of hematopoietic stem cell transplantation (HSCT) for MPS IH. Seven children with MPS IH at a median age of 1.5 years at the time of myeloablative HSCT were eligible. All patients had null mutations in IDUA gene. Iduronidase (0.58 mg/kg per dose) was administered intravenously in 11–14 weekly doses before HSCT and 8 weekly doses after HSCT. The infusions were well tolerated. All patients developed antibodies to Iduronidase but all engrafted with >90% donor hematopoiesis. A majority of patients had significant pulmonary complications before ERT and HSCT but all are alive and well with a median follow-up of more than 1 year after HSCT. This suggests that ERT prior to HSCT is unlikely to alter engraftment. In addition, morbidity was acceptable, despite a previous history of pulmonary difficulties that suggested that these patients were high risk for these complications. Therefore, we recommend treatment of MPS IH patients with combination of ERT and HSCT therapy to further investigate its potential to enhance outcomes with HSCT.
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pre stem cell transplantation enzyme replacement therapy in hurler syndrome does not lead to significant antibody formation or delayed recovery of the endogenous enzyme post transplant a case report
Pediatric Transplantation, 2007Co-Authors: Sandeep Soni, Chester B Whitley, Monica Hente, Nancy Breslin, Joseph H Hersh, Alexandra Cheerva, Salvatore BertoloneAbstract:Combined enzyme replacement therapy (ERT) and stem cell transplant (SCT) were done for a two year old boy with severe Hurler syndrome(HS) with the aim to decrease transplant related complications. He tolerated both the procedures well without any major complications. Urine glycosaminoglycans (GAGs) decreased post-transplant and child has improved clinically and neurologically. Insignificant titers of the anti-Iduronidase antibodies which developed post-transplant did not affect the transplant outcome or the endogenous recovery of the alpha-L-Iduronidase enzyme.
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cardiac findings after enzyme replacement therapy for mucopolysaccharidosis type i
American Journal of Cardiology, 2006Co-Authors: Elizabeth A Braunlin, James M Berry, Chester B WhitleyAbstract:Mucopolysaccharidosis type I is a lethal autosomal recessive storage disease caused by a deficiency of lysosomal α-l-Iduronidase and the consequent systemic accumulation of glycosaminoglycan. Cardiomyopathy and valvar insufficiency occur as glycosaminoglycan accumulates in the myocardium, expands the spongiosa of cardiac valves, and proliferates within the myointima of the epicardial coronary arteries. Congestive heart failure and death occur within the first decade of life in the most severe cases. Allogeneic hematopoietic stem cell transplantation, used in severe forms of the disease, markedly prolongs survival, alleviates ventricular hypertrophy, and preserves cardiac function, but cardiac valves continue to thicken and valvular insufficiency progresses. Enzyme replacement therapy with human recombinant α-l-Iduronidase has been proposed as an alternativee therapy for patients with mucopolysaccharidosis type I in whom the risk/benefit ratio of hematopoietic stem cell transplantation seems unfavorable. The investigators report the cardiac findings in a small series of 5 children with mucopolysaccharidosis type I who received enzyme replacement therapy for as long as 7 years. No deaths occurred during treatment. Left ventricular hypertrophy, which was present before therapy, resolved in all cases, and myocardial function remained normal. In contrast, the mitral and aortic valves remained thickened and, in some instances, developed progressive thickening and regurgitation. In conclusion, long-term enzyme replacement therapy has some clear benefits for the myocardium, but the cardiac valves appear unresponsive, and the ultimate effect on the coronary vasculature is unknown.
Patricia I Dickson - One of the best experts on this subject based on the ideXlab platform.
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specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis i
Molecular Genetics and Metabolism, 2012Co-Authors: Patricia I Dickson, Merry Passage, Moin Vera, Matthew N Ellinwood, Jillian R Brown, Robert G Witt, Brett E CrawfordAbstract:Abstract Intrathecal enzyme replacement therapy is an experimental option to treat central nervous system disease due to lysosomal storage. Previous work shows that MPS I dogs receiving enzyme replacement with recombinant human alpha- l -Iduronidase into the cisterna magna showed normal brain glycosaminoglycan (GAG) storage after three or four doses. We analyzed MPS I dogs that received intrathecal enzyme in a previous study using an assay that detects only pathologic GAG (pGAG). To quantify pGAG in MPS I, the assay measures only those GAG which display terminal iduronic acid residues on their non-reducing ends. Mean cortical brain pGAG in six untreated MPS I dogs was 60.9 ± 5.93 pmol/mg wet weight, and was 3.83 ± 2.64 in eight normal or unaffected carrier animals (p
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early versus late treatment of spinal cord compression with long term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type i
Molecular Genetics and Metabolism, 2010Co-Authors: Patricia I Dickson, Michael F Mcentee, Carole Vogler, Stephen Hanson, Charles H Vite, Anton Mlikotic, Agnes H Chen, Katherine P Ponder, Mark E Haskins, Brigette L TippinAbstract:Abstract Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-Iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested long-term and every 3-month intrathecal (IT) and weekly IV rhIDU in MPS I dogs age 12–15months (Adult) and MPS I pups age 2–23days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS I dogs were evaluated ( n =4 per group): IT+IV Adult, IV Adult, IT + IV Early, 0.58mg/kg IV Early and 1.57mg/kg IV Early. IT + IV rhIDU (Adult and Early) led to very high Iduronidase levels in cervical, thoracic, and lumber spinal meninges (3600–29,000% of normal), while IV rhIDU alone (Adult and Early) led to levels that were 8.2–176% of normal. GAG storage was significantly reduced from untreated levels in spinal meninges of IT + IV Early ( p p =.001), 0.58mg/kg IV Early ( p =.002) and 1.57mg/kg IV Early ( p
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immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis i
Journal of Clinical Investigation, 2008Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Maryn Peinovich, Thomas Lester, Steven Q Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Emil D. KakkisAbstract:Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-Iduronidase successfully reduces lysosomal storage in canines and humans with Iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-Iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to Iduronidase could improve the effectiveness of recombinant Iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to Iduronidase or left nontolerant. All canines received i.v. recombinant Iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed Iduronidase-specific antibodies that proportionally reduced in vitro Iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to Iduronidase improved the efficacy of enzyme replacement therapy with recombinant Iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.
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intrathecal enzyme replacement therapy successful treatment of brain disease via the cerebrospinal fluid
Molecular Genetics and Metabolism, 2007Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Carole Vogler, Beth Levy, Maryn Peinovich, Stephen Hanson, Emil D. KakkisAbstract:Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human Iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal Iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
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intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of mps i
Molecular Genetics and Metabolism, 2004Co-Authors: Patricia I Dickson, Michael F Mcentee, Carole Vogler, Beth Levy, Steven Q Le, E Kakkis, Pavel V Belichenko, William C Mobley, Stephen HansonAbstract:Abstract Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood–brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human α- l -Iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose–response study showed that doses of 0.46–4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of ∼1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of Iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
Michael F Mcentee - One of the best experts on this subject based on the ideXlab platform.
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replacing the enzyme α l Iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type i
Science Translational Medicine, 2010Co-Authors: Ashley Dierenfeld, Merry Passage, Michael F Mcentee, Carole Vogler, Charles H Vite, Agnes Chen, S Shah, J K Jens, Elizabeth M Snella, Karen L KlineAbstract:Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-Iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-Iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-Iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.
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early versus late treatment of spinal cord compression with long term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type i
Molecular Genetics and Metabolism, 2010Co-Authors: Patricia I Dickson, Michael F Mcentee, Carole Vogler, Stephen Hanson, Charles H Vite, Anton Mlikotic, Agnes H Chen, Katherine P Ponder, Mark E Haskins, Brigette L TippinAbstract:Abstract Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-Iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested long-term and every 3-month intrathecal (IT) and weekly IV rhIDU in MPS I dogs age 12–15months (Adult) and MPS I pups age 2–23days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS I dogs were evaluated ( n =4 per group): IT+IV Adult, IV Adult, IT + IV Early, 0.58mg/kg IV Early and 1.57mg/kg IV Early. IT + IV rhIDU (Adult and Early) led to very high Iduronidase levels in cervical, thoracic, and lumber spinal meninges (3600–29,000% of normal), while IV rhIDU alone (Adult and Early) led to levels that were 8.2–176% of normal. GAG storage was significantly reduced from untreated levels in spinal meninges of IT + IV Early ( p p =.001), 0.58mg/kg IV Early ( p =.002) and 1.57mg/kg IV Early ( p
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immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis i
Journal of Clinical Investigation, 2008Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Maryn Peinovich, Thomas Lester, Steven Q Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Emil D. KakkisAbstract:Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-Iduronidase successfully reduces lysosomal storage in canines and humans with Iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-Iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to Iduronidase could improve the effectiveness of recombinant Iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to Iduronidase or left nontolerant. All canines received i.v. recombinant Iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed Iduronidase-specific antibodies that proportionally reduced in vitro Iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to Iduronidase improved the efficacy of enzyme replacement therapy with recombinant Iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.
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intrathecal enzyme replacement therapy successful treatment of brain disease via the cerebrospinal fluid
Molecular Genetics and Metabolism, 2007Co-Authors: Patricia I Dickson, Merry Passage, Michael F Mcentee, Carole Vogler, Beth Levy, Maryn Peinovich, Stephen Hanson, Emil D. KakkisAbstract:Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human Iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal Iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
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intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of mps i
Molecular Genetics and Metabolism, 2004Co-Authors: Patricia I Dickson, Michael F Mcentee, Carole Vogler, Beth Levy, Steven Q Le, E Kakkis, Pavel V Belichenko, William C Mobley, Stephen HansonAbstract:Abstract Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood–brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human α- l -Iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose–response study showed that doses of 0.46–4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of ∼1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of Iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
