Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease.

Author: Hsu YH1,2, Liu RS3,4,5, Lin WL1,6, Yuh YS7,8, Lin SP9,10,11,12, Wong TT13,14,15,16
Affiliation: <sup>1</sup>Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 10617, Taiwan. <sup>2</sup>Department of Neurosurgery, Cheng-Hsin General Hospital, Taipei, Taiwan. <sup>3</sup>Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan. <sup>4</sup>National PET/Cyclotron Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. <sup>5</sup>Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan. <sup>6</sup>Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan. <sup>7</sup>Department of Pediatrics, Cheng-Hsin General Hospital, No.45, Cheng Hsin St., Pai-Tou, Taipei, 112, Taiwan. <sup>8</sup>Department of Pediatrics, National Defense Medical Center, Taipei, Taiwan. <sup>9</sup>Department of Medicine, MacKay Medical College, New Taipei City, Taiwan. <sup>10</sup>Department of Pediatrics, MacKay Memorial Hospital, No. 92, Sec. 2 Chung-Shan North Road, Taipei, 10449, Taiwan. <sup>11</sup>Department of Medical Research, MacKay Memorial Hospital, No. 92, Sec. 2 Chung-Shan North Road, Taipei, 10449, Taiwan. <sup>12</sup>Department of Early Childhood Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan. <sup>13</sup>Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. <sup>14</sup>Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan. <sup>15</sup>Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, 252 Wuxing St, Taipei, 11031, Taiwan. <sup>16</sup>Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
Conference/Journal: Orphanet J Rare Dis.
Date published: 2017 Jun 8
Other: Volume ID: 12 , Issue ID: 1 , Pages: 109 , Special Notes: doi: 10.1186/s13023-017-0649-6. , Word Count: 263

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.

KEYWORDS: Blood-brain barrier; Mucopolysaccharidosis type I; Recombinant human alpha-L-iduronidase; Ultrasound

PMID: 28595620 PMCID: PMC5465581 DOI: 10.1186/s13023-017-0649-6