Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysacchari
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RESEARCH
Open Access
Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease Yu-Hone Hsu1,2, Ren-Shyan Liu3,4,5, Win-Li Lin1,6, Yeong-Seng Yuh7,8, Shuan-Pei Lin9,10,11,12 and Tai-Tong Wong13,14,15,16*
Abstract Background: Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-Liduronidase (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. Keywords: Mucopolysaccharidosis type I, Blood-brain barrier, Ultrasound, Recombinant human alpha-L-iduronidase
Background Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder characterized by deficiency of alpha-Liduronidase (IDUA) and consequently inability to degrade glycosaminoglycan (GAG). The pathological accumulation of GAG systemically causes severe intellectual disability, * Correspondence: [email protected] 13 Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 14 Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan Full list of author information is available at the end of the article
cardiomyopathy, skeletal deformities, hepatosplenomegaly, and other organ dysfunctions. The life expectancy of patients with MPS I is less than 10 years. Enzyme replacement therapy with laronidase (a recombinant human alpha-L-iduronidase, rhIDU) has been shown to
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