Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia
Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia
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DOI：
10.1056/nejmoa1106173
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发表时间：
2012-03-08
影响因子：
158.5
通讯作者：
Landy, Hal
中科院分区：
文献类型：
--
作者：
Whyte, Michael P.;Greenberg, Cheryl R.;Landy, Hal
背景：组织非特异性碱性磷酸酶同工酶(TNSALP)基因突变是导致低磷症的主要原因。无机焦磷酸盐在细胞外堆积，导致软骨病或软骨病。受严重影响的婴儿通常因进行性胸部畸形或患有持续性骨病而死于呼吸功能不全。目前还没有得到批准的药物治疗。ENB-0040是一种骨靶向的重组人TNSALP，用于预防TNSALP基因敲除小鼠的低磷血症表现。方法我们招募了患有危及生命或衰弱的围产期或婴儿低磷血症的婴儿和幼儿，进行了一项关于ENB-0040治疗的多国开放标签研究。主要目标是软骨病的愈合，通过放射学分级进行评估。评价ENB-0040的运动和认知发育、呼吸功能和安全性，以及药物动力学和药效学。结果11例患者中，10例完成6个月的治疗，9例完成1年的治疗。9名患者在6个月后软骨病愈合，并伴有发育里程碑和肺功能的改善。TNSALP底物无机焦磷和吡哆醛5‘-磷酸升高的血浆水平降低。血清甲状旁腺激素的增加伴随着骨骼的愈合，通常需要饮食补钙。没有证据表明低钙血症、异位钙化或明确的药物相关严重不良事件。在48周的治疗中，4名患者出现了低滴度的抗eNB-0040抗体，没有明显的临床、生化或自身免疫异常。结论酶替代疗法SENB-0040可以改善危及生命的低磷酸盐血症婴儿和幼儿的骨骼X线片结果，改善肺和身体功能。(由Enobia Pharma和Shriners儿童医院资助；ClinicalTrials.gov编号，NCT00744042。)
BACKGROUNDHypophosphatasia 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.METHODSWe 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.RESULTSOf 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.CONCLUSIONSENB-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.)