First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient.

摘要: Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by deficiency of the enzyme β-glucuronidase (GUS), which required for degradation three glycosaminoglycans (GAGs): dermatan sulfate, heparan and chondroitin sulfate. Progressive accumulation these GAGs in lysosomes leads to increasing dysfunction numerous tissues organs. Enzyme replacement therapy (ERT) has been used successfully other MPS disorders, but there no approved treatment VII. Here we describe first human with recombinant GUS (rhGUS), an investigational 12-year old boy advanced stage Despite tracheostomy, nocturnal continuous positive airway pressure, oxygen therapy, significant pulmonary restriction obstruction led dependence end-tidal carbon dioxide (ETCO2) levels 60-80mmHg range, eventually approaching respiratory failure (ETCO2 100mmHg) need full-time ventilation. Since additional medical measures could improve his function, implemented experimental ERT infusing rhGUS at 2mg/kg over 4h every 2 weeks 24 weeks. Safety was evaluated standard assessments observance any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, dependence, CO2 cardiac valve liver spleen size, growth velocity were assessed evaluate response therapy. infusions well tolerated. No serious adverse events (SAEs) or IARs observed. After initiation infusions, patient's uGAG excretion decreased more than 50%. Liver size reduced within reached normal Pulmonary function appeared during course based on changes ETCO2 after off-ventilator challenges requirement. The patient regained ability eat orally, gained weight, energy activity increased. Over weeks, every-other-week tolerated SAEs, IARs, hypersensitivity measurable improvement objective clinical quality life.