Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the bloodbrain barrier (BBB). We recently reported that PerT-GUS, a form of β-glucuronidase (GUS) chemically modified to eliminate its uptake and clearance by carbohydrate-dependent receptors, crossed the BBB and cleared neuronal storage in an immunotolerant model of murine mucopolysaccharidosis (MPS) type VII. In this respect, the chemically modified enzyme was superior to native β-glucuronidase. Chemically modified enzyme was also delivered more effectively to heart, kidney, and muscle. However, liver and spleen, which express high levels of carbohydrate receptors, received nearly fourfold lower levels of PerT-GUS compared with native GUS. A recent report on PerT-treated sulfamidase in murine MPS IIIA confirmed enhanced delivery to other tissues but failed to observe clearance of storage in neurons. To confirm and extend our original observations, we compared the efficacy of 12 weekly i.v. infusions of PerT-GUS versus native GUS on (i) delivery of enzyme to brain; (ii) improvement in histopathology; and (iii) correction of secondary elevations of other lysosomal enzymes. Such correction is a recognized biomarker for correction of neuronal storage. PerT-GUS was superior to native GUS in all three categories. These results provide additional evidence that long-circulating enzyme, chemically modified to escape carbohydrate-mediated clearance, may offer advantages in treating MPS VII. The relevance of this approach to treat other lysosomal storage diseases that affect brain awaits confirmation.beta-glucuronidase deficiency | glycosaminoglycans | mannose 6-phosphate receptor | mannose receptor M ucopolysaccharidosis type VII (MPS VII or Sly syndrome) belongs to a group of lysosomal storage disorders (LSDs), each caused by deficiency of a lysosomal enzyme. In this case, the missing enzyme is β-glucuronidase (GUS), which catalyzes the degradation of the glycosaminoglycans (GAGs) dermatan sulfate, heparan sulfate, and chondroitin sulfate (1). In MPS VII cells, the undegraded substrates gradually accumulate in lysosomes, causing progressive lysosomal, cellular, and ultimately organ, dysfunction. Affected patients display delayed development, organomegaly, skeletal and cardiac abnormalities, and mental retardation (2). The age of onset and severity of disabilities are quite variable. Enzyme replacement therapy (ERT) has been successful in clearing storage materials from the viscera and in improving clinical pathologies in patients with other LSDs such as Gaucher disease (3), Fabry disease (4-6), Pompe disease (7-9), MPS I (10), MPS II (11), and MPS VI (12). However, delivery of enzyme to the brain is compromised by the selective and limited permeability of the blood-brain barrier (BBB) (13). Because many LSDs, such as MPS VII, affect the central nervous system (CNS), designing a therapy that can traverse the BBB and clear neuronal stor...
Supervision is an important factor in reducing injury risk. There are multiple factors that can affect the appropriate level of supervision including risk perception, anticipation of injury, and distracted behaviors. This study examined the perceived risks of child injury among parents and child caregivers and their supervision behavior among adults in an urban playground. Participant data from 25 individuals were collected through observations and anonymous self-reported surveys. More than half of the participants indicated practice of appropriate supervisory behavior, including attentiveness to their child's behavior and proximity to their child during play. Caregivers were more likely to report more careful levels of supervision. One-fourth of participants reported a change in the supervisory behavior during periods of distraction, specifically with phone use. Of the variables tested, there was a significant association between the variable 'talking to other adults' during supervision and 'prior injury' (P value = 0.04, 95% CI 0.03-0.91). Parents were more likely to report that they would leave their child unattended if they believed that the playground was a safe environment for play. There was a difference between self-reported behaviors and actual observed behavior, which is likely due to varying perspectives regarding child safety and injury prevention. In regards to injury risk, findings highlight the important role of appropriate supervisory behaviors and risk perceptions in preventing child injuries.
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