Browsing by Author "Kishnani, PS"

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    A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease
    (Molecular Genetics and Metabolism Reports, 2017-07-24) Lim, H-H; Yi, H; Kishimoto, TK; Gao, F; Sun, B; Kishnani, PS
    A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa) during the first 3 weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX) per week for the first 3 weeks. Empty nanoparticles (NP) were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Body weight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes.
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    Language and speech function in children with infantile Pompe disease
    (Journal of Pediatric Neurology, 2009-01-01) Muller, CW; Jones, HN; O'Grady, G; Suárez, HA; Heller, JH; Kishnani, PS
    Pompe disease, also known as glycogen storage disease type II and acid maltase deficiency, is a rare autosomal recessive progressive neuromuscular disorder. The natural course of the infantile form of this condition has resulted in mortality for patients prior to 1 year of age, making investigations into language and speech function in this population impossible. However, with the advent of treatment with enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme®), the lifespan of children with this condition has been extended. A retrospective study of the language and speech skills of 12 children enrolled in clinical trials for treatment with ERT at a tertiary care center was completed. Standardized language assessment instruments were administered to all participants, and six of the 12 were assessed twice. At initial assessment, overall language function was found to be age appropriate in 58% of participants, while, in those who received reassessment, overall normal language function was seen in 83%. Speech assessments were completed during all visits in which subjects were 24 months or older. Articulatory disorders and/or hypernasality were commonly encountered and were exhibited in 82% of speech assessments. Disorders in language and/or speech were found in all participants at some point in the course of the study. Overall, language delays tended to improve with time. Speech disorders were encountered more commonly, were often severe, and appeared to be motoric in nature. Children with infantile Pompe disease treated with ERT appear to be at high risk for speech disorders in particular. Further systematic investigations are needed. © 2009 IOS Press. All rights reserved.
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    Oropharyngeal Dysphagia in Infants and Children with Infantile Pompe Disease.
    (Dysphagia, 2009-09) Jones, HN; Muller, CW; Lin, M; Banugaria, SG; Case, LE; Li, JS; O'Grady, G; Heller, JH; Kishnani, PS
    Pompe disease is a rare genetic progressive neuromuscular disorder. The most severe form, infantile Pompe disease, has historically resulted in early mortality, most commonly due to cardiorespiratory failure. Treatment with enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme((R))) has extended the lifespan of individuals with this disease. With the introduction of ERT and the resultant improved survival, dysphagia is being encountered clinically with increasing regularity though systematic data remain unavailable. We retrospectively studied the oropharyngeal swallowing of 13 infants and children with Pompe disease using videofluoroscopy before initiation of ERT, allowing for baseline swallow function to be established in an untreated cohort. Dysphagia was present in all 13 subjects, even in a participant only 15 days old. Oral stage signs were present in 77%, most frequently a weak suck in 69%. Pharyngeal stage signs were present in 100%, including a pharyngeal swallow delay in 92% and pharyngeal residue in 77%. Airway invasion was present in 76.9% of subjects, including penetration in five (38.46%) and silent aspiration in an additional five (38.46%). No relationship in the relative involvement of swallowing, gross motor function, and cardiac disease appeared to be present.