Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy

Chen, Yonghong; Zheng, Shusen; Tecedor, Luis; Davidson, Beverly L.

doi:10.1016/j.ymthe.2018.01.010

Cited by 14 publications

(16 citation statements)

References 34 publications

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“…Thus, the intrinsic biochemical properties has to be closely considered when to assess the applicability of the chemical modification approach for other lysosomal enzymes. The recombinant Sulfamidase produced in this study was remarkably stable, and both rhSulfamidase and CM-rhSulfamidase appeared to be retained within the cells, which agrees with studies of sulfamidase being poorly secreted from transduced cells [8,25]. The strong intracellular retention and stability may be key features enabling effective intra-lysosomal concentrations of CM-rhSulfamidase in CNS after repeated administration.…”

Section: Discussionsupporting

confidence: 86%

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Gustavsson

Sjöström

Tjernberg

et al. 2019

Molecular Genetics and Metabolism Reports

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Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) characterized by severe central nervous system (CNS) degeneration. The disease is caused by mutations in the SGSH gene coding for the lysosomal enzyme sulfamidase. Sulfamidase deficiency leads to accumulation of heparan sulfate (HS), which triggers aberrant cellular function, inflammation and eventually cell death. There is currently no available treatment against MPS IIIA. In the present study, a chemically modified recombinant human sulfamidase (CM-rhSulfamidase) with disrupted glycans showed reduced glycan receptor mediated endocytosis, indicating a non-receptor mediated uptake in MPS IIIA patient fibroblasts. Intracellular enzymatic activity and stability was not affected by chemical modification. After intravenous (i.v.) administration in mice, CM-rhSulfamidase showed a prolonged exposure in plasma and distributed to the brain, present both in vascular profiles and in brain parenchyma. Repeated weekly i.v. administration resulted in a dose- and time-dependent reduction of HS in CNS compartments in a mouse model of MPS IIIA. The reduction in HS was paralleled by improvements in lysosomal pathology and neuroinflammation. Behavioral deficits in the MPS IIIA mouse model were apparent in the domains of exploratory behavior, neuromuscular function, social- and learning abilities. CM-rhSulfamidase treatment improved activity in the open field test, endurance in the wire hanging test, sociability in the three-chamber test, whereas other test parameters trended towards improvements. The unique properties of CM-rhSulfamidase described here strongly support the normalization of clinical symptoms, and this candidate drug is therefore currently undergoing clinical studies evaluating safety and efficacy in patients with MPS IIIA.

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Section: Discussionsupporting

confidence: 86%

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Gustavsson

Sjöström

Tjernberg

et al. 2019

Molecular Genetics and Metabolism Reports

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“…To test whether this is an effect of overexpression of transgenes in animals null for a disease gene, we subsequently examined brain sections from mucopolysaccharidosis type IIIA (MPS IIIA) sulfamidase (SGSH) homozygous knockout mice treated with AAV4 expressing human SGSH, a secreted protein, using the same dose, injection coordinates, and volume as in our AAV4.GRN studies. 51 There was no observed toxicity in treated MPS IIIA mice (data not shown), supporting an effect specific to GRN.…”

Section: A T Cell-mediated Inflammatory Response Precedes Neuronal Lomentioning

confidence: 67%

“…with AAV4.SGSH, a secreted protein, using the same approach as our study, showed no sign of hippocampal or ventricular degeneration or of cellular infiltrate. 51 Cumulatively, the data suggest that our results are specific to overexpression of GRN as a target gene, rather than route of delivery, dose, expression of a human gene in a null mouse model, or expression of a secreted protein.…”

Section: Discussionmentioning

confidence: 83%

“…All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. MPS IIIA Sgsh null and heterozygous mice were generated and maintained as previously described, 51 and studies were approved by the Institutional Animal Care and Use Committee of CHOP.…”

Section: Micementioning

confidence: 99%

“…MPS IIIA Sgsh null and heterozygous mice were injected at 2 months and euthanized at 5.5 months, as previously described. 51…”

Section: Stereotaxic Deliverymentioning

confidence: 99%

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AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity

et al. 2019

Self Cite

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Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRNdeficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.

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Techniques for Intracranial Stereotaxic Injections of Adeno‐Associated Viral Vectors in Adult Mice

Keiser

Davidson

2018

CP Mouse Biology

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Stereotaxic intracranial injection of viral vectors is a valuable technique to directly deliver genetic material to a specific population of cells in the central nervous system of a mouse model. This enables scientists to test candidate gene therapies or disease modulators that can then provide insight into the pathological mechanisms of disease. In this article, we present a standardized method of conducting intracranial stereotaxic injection of adeno‐associated virus into a specific brain region in a mouse model. Support protocols are provided for virus dialysis and testing new stereotaxic coordinates with dye. © 2018 by John Wiley & Sons, Inc.

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Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy

Cited by 14 publications

References 34 publications

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity

Techniques for Intracranial Stereotaxic Injections of Adeno‐Associated Viral Vectors in Adult Mice

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