Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type i disease
Journal
Orphanet Journal of Rare Diseases
Journal Volume
12
Journal Issue
1
Date Issued
2017
Author(s)
Abstract
Background: Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB). Methods: We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain. Results: Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme. Conclusions: Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy. ? 2017 The Author(s).
Subjects
Blood-brain barrier; Mucopolysaccharidosis type I; Recombinant human alpha-L-iduronidase; Ultrasound
SDGs
Other Subjects
Evans blue; laronidase; levo iduronidase; recombinant protein; animal tissue; Article; blood brain barrier; comparative effectiveness; controlled study; drug brain level; drug distribution; drug transport; drug uptake; echoencephalography; enzyme activity; enzyme replacement; hemisphere; Hurler syndrome; microbubble; mouse; nonhuman; normal value; transcranial pulsed ultrasound; animal; C57BL mouse; enzyme replacement; gene knock-in; Hurler syndrome; procedures; transport at the cellular level; ultrasound; Animals; Biological Transport; Enzyme Replacement Therapy; Gene Knock-In Techniques; Iduronidase; Mice; Mice, Inbred C57BL; Mucopolysaccharidosis I; Recombinant Proteins; Ultrasonic Waves
Type
journal article