miR-143 regulates lysosomal enzyme transport across blood-brain barrier and improves CNS treatment for Hurler syndrome

The adult blood–brain barrier, unlike the neonatal blood–brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood–brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood–brain barrier ((±)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human β-glucuronidase. In 8-week-old adult mice, manipulations with (±)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human β-glucuronidase was inhibited by mannose 6-phosphate for the agents (±)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human β-glucuronidase across the blood–brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human β-glucuronidase transport at the adult blood–brain barrier.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1222742110 ◽

2013 ◽

Vol 110 (8) ◽

pp. 2999-3004 ◽

Cited By ~ 87

Author(s):

D. Wang ◽

S. S. El-Amouri ◽

M. Dai ◽

C.-Y. Kuan ◽

D. Y. Hui ◽

...

Keyword(s):

Blood Brain Barrier ◽

Receptor Binding ◽

Lysosomal Enzyme ◽

Binding Domain ◽

Brain Barrier ◽

Receptor Binding Domain ◽

Blood Brain

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Enhanced lysosomal enzyme delivery across the blood-brain barrier by modulating the valency of ICAM-1-targeted nanocarriers

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2015.12.351 ◽

2016 ◽

Vol 117 (2) ◽

pp. S77

Author(s):

Rachel L. Manthe ◽

Edward H. Schuchman ◽

Silvia Muro

Keyword(s):

Blood Brain Barrier ◽

Lysosomal Enzyme ◽

Brain Barrier ◽

Blood Brain ◽

Enzyme Delivery

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Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice

Science Translational Medicine ◽

10.1126/scitranslmed.aay1163 ◽

2020 ◽

Vol 12 (545) ◽

pp. eaay1163 ◽

Cited By ~ 16

Author(s):

Julie C. Ullman ◽

Annie Arguello ◽

Jennifer A. Getz ◽

Akhil Bhalla ◽

Cathal S. Mahon ◽

...

Keyword(s):

Blood Brain Barrier ◽

Lysosomal Enzyme ◽

Brain Barrier ◽

Enzyme Treatment ◽

Brain Delivery ◽

In Vivo Models ◽

Blood Brain ◽

Brain Exposure ◽

Transport Vehicle ◽

The Brain

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

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