Retroviral vector design studies toward hematopoietic stem cell gene therapy for mucopolysaccharidosis type I

Pan, Dao; Aronovich, Elena L.; McIvor, R. Scott; Whitley, Chester B.

doi:10.1038/sj.gt.3301298

Cited by 17 publications

(21 citation statements)

References 51 publications

(48 reference statements)

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“…5,6,36 In such cases, besides gradual cell replacement in brain, it is not clear if IDUA expressed at wild-type levels can be secreted in sufficient amounts and be internalized/ used by neighboring deficient cells. It is known that peripheral blood mononuclear cells from normal individuals release minimum levels of IDUA in vitro, 37 although IDUA from enzymeoverexpressing brain macrophages was critical to achieving complete correction of CNS disease manifestations in MPS I mice after HSC-mediated gene therapy. 9 Compared to enzyme-producing donor cells migrated inside the CNS of MPS/WT group, BBB-targeted IDUAe protein delivered at moderate levels in the circulation (in MPS/IDUAe-M) successfully introduced comparable levels of IDUA activities in cerebrum.…”

Section: Discussionmentioning

confidence: 99%

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

et al. 2014

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Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.

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Section: Discussionmentioning

confidence: 99%

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

et al. 2014

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“…To determine the accessibility of IDUA for genetic modification, a human myc tag (Table S1) was fused in-frame to the 5′-or 3′ end of the human IDUA coding sequence (19). The addition of myc tag at C terminus (IDUA3′Myc), but not at the N terminus (IDUA5′Myc), as expected, had no effect on IDUA catalytic function or its trafficking to the extracellular space (Fig.…”

Section: Resultsmentioning

confidence: 99%

Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood–brain barrier

Wang¹,

El‐Amouri²,

Dai³

et al. 2013

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

139

119

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To realize the potential of large molecular weight substances to treat neurological disorders, novel approaches are required to surmount the blood-brain barrier (BBB). We investigated whether fusion of a receptor-binding peptide from apolipoprotein E (apoE) with a potentially therapeutic protein can bind to LDL receptors on the BBB and be transcytosed into the CNS. A lysosomal enzyme, α-L-iduronidase (IDUA), was used for biological and therapeutic evaluation in a mouse model of mucopolysaccharidosis (MPS) type I, one of the most common lysosomal storage disorders with CNS deficits. We identified two fusion candidates, IDUAe1 and IDUAe2, by in vitro screening, that exhibited desirable receptor-mediated binding, endocytosis, and transendothelial transport as well as appropriate lysosomal enzyme trafficking and biological function. Robust peripheral IDUAe1 or IDUAe2 generated by transient hepatic expression led to elevated enzyme levels in capillary-depleted, enzyme-deficient brain tissues and protein delivery into nonendothelium perivascular cells, neurons, and astrocytes within 2 d of treatment. Moreover, 5 mo after long-term delivery of moderate levels of IDUAe1 derived from maturing red blood cells, 2% to 3% of normal brain IDUA activities were obtained in MPS I mice, and IDUAe1 protein was detected in neurons and astrocytes throughout the brain. The therapeutic potential was demonstrated by normalization of brain glycosaminoglycan and β-hexosaminidase in MPS I mice 5 mo after moderate yet sustained delivery of IDUAe1. These findings provide a noninvasive and BBB-targeted procedure for the delivery of largemolecule therapeutic agents to treat neurological lysosomal storage disorders and potentially other diseases that involve the brain.in vivo evaluation | LDL receptor-related protein 1 | lysosomal storage diseases | neurological disorders | CNS protein delivery

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“…Mouse genomic DNA diluted in water was used as a standard curve for Gapdh . The standard curve for IDUA consisted of serial dilutions of DNA isolated from a clone of NIH3T3 cells transduced at low multiplicity with LP1CD retroviral vector (Pan et al, 2000) and assumed to contain 1 viral integrant per cell containing IDUA . This DNA was diluted in wild-type C57BL/6 liver DNA to make serial dilutions.…”

Section: Methodsmentioning

confidence: 99%

Direct gene transfer to the CNS prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type I

Wolf

Lenander

Nan

et al. 2011

Neurobiology of Disease

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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 40x 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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Retroviral vector design studies toward hematopoietic stem cell gene therapy for mucopolysaccharidosis type I

Cited by 17 publications

References 51 publications

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood–brain barrier

Direct gene transfer to the CNS prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type I

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