Enzyme replacement in a canine model of Hurler syndrome.

Shull, Robert M.; Kakkis, Emil; McEntee, Michael F.; Kania, Stephen A.; Jonas, Adam J.; Neufeld, Elizabeth F.

doi:10.1073/pnas.91.26.12937

Cited by 153 publications

(96 citation statements)

References 30 publications

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“…7,8 Laronidase (recombinant human ␣-L-iduronidase) infusions reduce abnormal and excessive GAG deposits in several tissues, resulting in decreases in hepatomegaly and urinary GAG excretion and improvements in upper airway obstruction as well as lung function tests. 7,8 However, a limitation of intravenous ERT is its inability to cross the blood brain barrier 9 ; hence, it is not predicted to help the central nervous system directly. …”

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confidence: 99%

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome

Grewal

Wynn

Abdenur

et al. 2005

Genetics in Medicine

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Purpose: Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. Methods: Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol. Results: The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related

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confidence: 99%

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome

Grewal

Wynn

Abdenur

et al. 2005

Genetics in Medicine

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“…Studies in animal models have been seminal to the translation of ERT to patients. Canine MPSI was treated at Ն5.5 months of age with the recombinant human form of the missing enzyme ␣-Liduronidase (21,22). Whereas storage decreased in some visceral tissues, there was no improvement in the heart valves up to 13 months of age after long-term low doses or short-term higher doses.…”

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confidence: 99%

Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

Schuldt

Hampton

Chu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Cardiovascular manifestations of lysosomal storage disease (LSD) are a significant health problem for affected patients. Infantileonset cardiac disease, because of its rapid progression, is usually treated symptomatically. Therapy in older patients includes valve replacement and bone marrow (BM) transplantation, both of which are life threatening in the already debilitated patients. Enzyme replacement therapy has potential benefit but has not yet been demonstrated to provide long-term relief for cardiac disease. Here, we demonstrate prevention of severe cardiac manifestations in ␤-glucuronidase (GUSB) null mice BM-transplanted i.v. as neonates without myeloablative pretreatment. The mice, a model of mucopolysaccharidosis type VII (MPSVII, Sly syndrome), develop progressive LSD unless provided with GUSB early in life. The BM recipients retained GUSB؉ donor cells in the peripheral blood and heart until necropsy at >11 months of age. The enzyme ␤-hexosamindase increased in tissues of GUSB null MPSVII mice was reduced significantly (P ‫؍‬ 0.001) in treated MPSVII hearts. Electrocardiography demonstrated normalization of heart rate, PR, PQ, and QRS intervals in BM recipients. Storage was markedly reduced in the stroma of heart valves, adventitial cells of the aortic root, perivascular and interstitial cells of the myocardium, and interstitial cells of the conduction tissue. Heart͞body weight ratio normalized. The aortic root was still grossly distended, and the conductive myocytes retained storage, suggesting neither plays a major role in ECG normalization. We conclude that transplantation of MPSVII neonates without toxic intervention can prevent many of the cardiovascular manifestations of LSD.

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“…The normal and MPS I canines treated with a control or ineffective regimen had a mean ELISA titer at week 12 of 149 OD͞ l, compared with an ELISA titer of 7.2 OD͞ l for canines receiving the successful tolerance regimen, a 20-fold difference ( Table 1). The reduced IgG immune response observed with this regimen has not been observed in over 10 yr of studies of the immune response to rhIDU replacement therapy in this colony (6,22) (data not shown).…”

Section: A Tolerance Induction Regimen Combining Low-dose Enzyme Infu-mentioning

confidence: 95%

“…The adverse impact of antibodies on enzyme replacement therapy of lysosomal storage disorders has been documented in the canine model of MPS I. MPS I-affected canines (4) have a null genotype (5) and, during infusions with rhIDU, mount strong antibody responses that can lead to IgG-mediated complement activation and cause anaphylactoid reactions (6). Antibodies may also alter clearance from the circulation and may reduce the efficiency of enzyme uptake in tissues based on in vitro (unpublished data) and in vivo studies (7).…”

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confidence: 99%

Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I

Kakkis

Lester

Yang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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 ␣-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 ␣-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 receptormediated uptake because ␣-L-iduronidase and ␣-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated ␣-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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Enzyme replacement in a canine model of Hurler syndrome.

Cited by 153 publications

References 30 publications

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome

Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I

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