Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-<i>N</i>-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts

Kan, Shinichi; Troitskaya, L. A.; Sinow, Carolyn; Haitz, Karyn; Todd, Amanda K.; Stefano, Ariana Di; Le, Steven Q.; Dickson, Patricia I.; Tippin, Brigette L.

doi:10.1042/bj20130845

Cited by 40 publications

(59 citation statements)

References 45 publications

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“…1A). High mannose chains were also lacking, in agreement with a previous report (11). NAGLU-IGFII, but not unmodified NAGLU, was bound to domains 10-13 of the Man6-P/IGFII receptor, as determined by a competitive binding assay (Fig.…”

Section: Igfii-modified Enzyme Binds To the Igfii Receptor And Is Endsupporting

confidence: 78%

“…with no Man6-P have been made for β-glucuronidase (20), α-glucosidase (21), and NAGLU (11), and shown to have enzymatic activity similar to that of the original lysosomal enzyme and to be taken up by cultured cells in a manner that is dependent on IGFII and independent of Man6-P. In addition, the β-glucuronidaseand α-glucosidase-IGFII fusion proteins, administered i.v.…”

Section: Significancementioning

confidence: 99%

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Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

Kan

Aoyagi-Scharber

et al. 2014

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

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106

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Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the bloodbrain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/ IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB. M ucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a heritable lysosomal disorder of heparan sulfate degradation, divided into four types (A-D), depending on the enzyme deficiency (1, 2). All four MPS III types are characterized by severe neurologic problems and relatively mild somatic ones. Profound intellectual disability that progresses to dementia, behavioral disturbances, and death in the second or third decade bring untold suffering to the MPS III patients and their families. Despite the dire need, treatment for the MPS III disorders has lagged behind other MPS diseases. Hematopoietic stem cell transplantation, an effective procedure for MPS I patients with CNS involvement (3), is not effective for MPS III (4). Enzyme replacement therapy has been available for some years for several MPS with extensive somatic involvement [MPS I (5, 6), II (7), and VI (8)], or is newly approved (MPS IVA), or in clinical trial (MPS VII). However, development of enzyme replacement for MPS III did not seem promising because access to therapeutic enzyme to brain parenchyma would be limited by the blood-brain barrier. With respect to MPS IIIB, a deficiency of α-N-acetylglucosaminidase, EC 3.2.1.50) (NAGLU), there is an additional difficulty in that, in contrast to ...

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Section: Igfii-modified Enzyme Binds To the Igfii Receptor And Is Endsupporting

confidence: 78%

Section: Significancementioning

confidence: 99%

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

Kan

Aoyagi-Scharber

et al. 2014

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

Self Cite

106

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“…When infused directly into a cerebral ventricle of Sanfilippo type B ( Naglu −/− ) mice, a modified form of NAGLU (NAGLU-IGF2), comprising human NAGLU recombinantly fused to insulin-like growth factor 2 (IGF2) for IGF2/mannose 6-phosphate (M6P) receptor-mediated enhanced lysosomal targeting,21, 22, 23 results in marked enzyme uptake in the brain 20 . ICV administration of NAGLU-IGF2 cleared the pathologic storage of partially degraded HS in the brain with no sign of re-accumulation for at least 1 month after the last dose and reduced secondary accumulations of previously identified pathologic markers, such as β-hexosaminidase and lysosome-associated membrane protein 1 (LAMP1) 20, 24, 25, 26, 27.…”

Section: Introductionmentioning

confidence: 99%

Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice

Aoyagi-Scharber

Crippen-Harmon

Lawrence

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu−/− mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu−/− mice were treated with 1–100 μg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 μg doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu−/− mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu−/− mouse brain.

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“…35 Also, fusion proteins that could enhance the ability of a large enzyme to cross the BBB have been explored in MPS I, MPS II, and MPS IIIB (i.e., monoclonal antibody against the human insulin or transferrin receptor and insulin-like growth factor-II). [36][37][38] Finally, new approaches like direct delivery of ERT via the cerebrospinal fluid by intracerebroventricular or intrathecal injection, or via the parenchyma by intracerebral injections, seem to be, although highly invasive, promising in ameliorating the neurodegeneration in MPS. 29,39,40…”

Section: Challenges Of Ert Neurocognitive Diseasementioning

confidence: 99%

Causal Therapies in Mucopolysaccharidoses: Enzyme Replacement Therapy

Vartanyan

Montaño

2018

JCS

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Enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) is the treatment of choice for patients, since it specifically addresses the underlying cause of the disease. Intravenous weekly infusions of recombinant enzymes for MPS I, II, IVA, VI, and VII have proven to be safe and efficacious for somatic symptoms. ERT has been shown to decrease urinary glycosaminoglycan levels and organomegaly, while improving stamina of patients, respiratory function, and quality of life. Although early administration of ERT optimizes outcomes, adult patients still benefit from treatment. ERT has been successfully used as combination therapy with hematopoietic stem cell transplant for patients with MPS I and MPS II, improving patient's cognitive outcomes. Although patients can receive benefit from ERT, current challenges include lack of improvement of neurological manifestations, limited effect on bone disease, development of immune response toward the infused enzyme, and high cost. We will discuss the milestones achieved by intravenous ERT for MPS diseases as well as the current challenges.

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Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts

Cited by 40 publications

References 45 publications

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice

Causal Therapies in Mucopolysaccharidoses: Enzyme Replacement Therapy

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