Michael B Bober

Publications (2)55.83 Total impact

• Source

  Available from: Mohamed A Hamdan

  Article: Enzyme-replacement therapy in life-threatening hypophosphatasia.

  Michael P Whyte, Cheryl R Greenberg, Nada J Salman, Michael B Bober, William H McAlister, Deborah Wenkert, Bradley J Van Sickle, Jill H Simmons, Terence S Edgar, Martin L Bauer, [......], Robert H Cleveland, William R Cranley, Ruth Lim, Tom D Thacher, Jill E Mayhew, Matthew Downs, José Luis Millán, Alison M Skrinar, Philippe Crine, Hal Landy
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  ABSTRACT: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).
  New England Journal of Medicine 03/2012; 366(10):904-13. · 53.30 Impact Factor
• Article: Respiratory mechanics in an infant with perinatal lethal hypophosphatasia treated with human recombinant enzyme replacement therapy.

  Elena Rodriguez, Michael B Bober, Lauren Davey, Arlene Zamora, Annelise B Li Puma, Aaron Chidekel, Thomas H Shaffer
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  ABSTRACT: Hypophosphatasia is a rare autosomal recessive disorder caused by deficient activity of tissue nonspecific alkaline phosphatase (TNSALP) and characterized by defective bone mineralization. In the perinatal lethal form, respiratory complications due to rachitic deformities of the thoracic cage and associated hypoplastic lungs are present. ENB-0040 is a bone-targeted human recombinant TNSALP fusion protein that aims to restore skeletal mineralization. The goal of this study was to characterize pulmonary and thoracic cage mechanics in an infant with the perinatal lethal form of hypophosphatasia under enzyme replacement therapy. Pulmonary function testing was performed on a preterm, 8-week-old patient with hypophosphatasia who was mechanically ventilated since birth because of severe chest wall insufficiency. The measurements consisted of respiratory impulse oscillation measurements (resistance and reactance), ventilatory mechanics (compliance and resistance), and thoracoabdominal motion (TAM) analysis. At baseline, chest wall compliance was 50% of normal, and the TAM indicated predominantly abdominal displacement. After 12 weeks of treatment, a consistent decrease in ventilator requirements and improvement in lung function and chest wall mechanics were observed and correlated with thoracic cage radiologic findings. Measurable changes in chest wall dynamics and respiratory mechanics using noninvasive technology were useful for respiratory management and therapeutic guidance of ENB-0040 treatment in this patient.
  Pediatric Pulmonology 02/2012; 47(9):917-22. · 2.53 Impact Factor