RESUMO
Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme ß-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGs): dermatan sulfate, heparan sulfate, and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy with advanced stage MPS VII. Despite a tracheostomy, nocturnal continuous positive airway pressure, and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence and end-tidal carbon dioxide (ETCO2) levels in the 60-80mmHg range, eventually approaching respiratory failure (ETCO2 of 100mmHg) and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2mg/kg over 4h every 2 weeks for 24 weeks. Safety was evaluated by standard assessments and observance for any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity were assessed to evaluate response to therapy. rhGUS infusions were well tolerated. No serious adverse events (SAEs) or IARs were observed. After initiation of rhGUS infusions, the patient's uGAG excretion decreased by more than 50%. Liver and spleen size were reduced within 2 weeks of the first infusion and reached normal size by 24 weeks. Pulmonary function appeared to improve during the course of treatment based on reduced changes in ETCO2 after off-ventilator challenges and a reduced oxygen requirement. The patient regained the ability to eat orally, gained weight, and his energy and activity levels increased. Over 24 weeks, treatment with every-other-week infusions of rhGUS was well tolerated with no SAEs, IARs, or hypersensitivity reactions and was associated with measurable improvement in objective clinical measures and quality of life.
Assuntos
Terapia de Reposição de Enzimas , Glucuronidase/administração & dosagem , Glucuronidase/uso terapêutico , Mucopolissacaridose VII/tratamento farmacológico , Administração Intravenosa , Peso Corporal/efeitos dos fármacos , Criança , Dermatan Sulfato/urina , Glucuronidase/efeitos adversos , Glucuronidase/genética , Glicosaminoglicanos/urina , Heparitina Sulfato/urina , Hepatomegalia/tratamento farmacológico , Hepatomegalia/patologia , Humanos , Masculino , Mucopolissacaridose VII/patologia , Mucopolissacaridose VII/fisiopatologia , Qualidade de Vida , Esplenomegalia/tratamento farmacológico , Esplenomegalia/patologia , Terapias em EstudoRESUMO
OBJECTIVES: The aim of this study was to compare two modes of airway clearance, the intrapulmonary percussive ventilation system (IPV) to high frequency chest wall oscillation system (HFCWO) in medically complex pediatric patients with tracheostomy requiring long term care. METHODS: This was a single center, retrospective study comparing the number of respiratory illnesses, lower respiratory tract infections (LRTI), utilization of bronchodilator and systemic steroids, and respiratory illnesses requiring acute care hospitalizations. A total of 8 tracheostomy dependent patients between the ages of 1-22 years were included for a 2-year study period. Each patient was used as their own control. During the period studied, the only variable in the medical regimen was the modality used for airway clearance. A Poisson regression model and generalized estimating equations were used to compare pre and post rates and to account for the correlation of count data from the same individual. Additionally, the paired differences (post-pre) for each event count were computed to provide the median and range of reductions in event rates while using intrapulmonary percussive ventilation system device. The non-parametric wilcoxon signed-rank test employed to determine whether the results from the Poisson model were consistently observed regardless of method of analysis. RESULTS: The total number of respiratory illnesses were reduced from 32 per year on HFCWO therapy to 15 per year on IPV system therapy (p < 0.001). The total number of LRTI requiring antibiotic use were decreased from 15 per year to 6 per year (p = 0.01), use of bronchodilator treatments were reduced from 53 to 21 (p < 0.001) and utilization of systemic steroids were reduced from 12 to 4 on IPV (p = 0.003). Numbers of hospitalizations to acute care facilities were reduced from 8 to 3 hospitalizations during the period of IPV use for airway clearance (p = 0.003). CONCLUSION: This study suggests that airway clearance by IPV therapy could be more effective and beneficial in providing airway clearance in specific subsets of the medically complex pediatric population.