Phase 2 of Growth Hormone for Treatment of Albright Hereditary Osteodystrophy

生长激素治疗奥尔布赖特遗传性骨营养不良症的第二阶段

• 批准号: 8320750
• 负责人: EMILY L GERMAIN-LEE
• 金额: $ 9.65万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320750
• 关键词: Phase; Growth; Hormone; Treatment; Albright

DESCRIPTION (provided by applicant): Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in the gene encoding the a chain of stimulatory gene proteins (Gs). Among other abnormalities, it is associated with short stature and obesity. Because of tissue-specific imprinting, patients with GNAS mutations on maternally inherited alleles are resistant to multiple G protein-coupled hormones, a variant termed pseudohypoparathyroidism type 1a (PHP1a). Patients who inherit mutations from the paternal allele have a similar phenotype but without hormonal resistance, termed pseudopseudohypo- parathyroidism (PPHP). The investigators hypothesized that PHP1a patients are resistant to growth hormone releasing hormone and found that approximately two-thirds are growth hormone (GH) deficient. GH therapy has led to increased growth velocities, taller adult heights, decreased BMI and adiposity, and improvements in lipids, bone density, sense of well-being, and self-esteem without any significant side effects from GH use. However, GH deficiency is not the only cause of the short stature in PHP1a. Premature fusion of the epiphyses reflected in advanced bone ages is also a cause and occurs in patients with PHP1a who are GH-sufficient as well as in patients with PPHP. In vitro and mouse studies have implicated that haploinsufficiency of G protein in chondrocytes in PHP1a and PPHP causes premature chondrocyte differentiation which could be the etiology. Based on the promising results with the GH trial in GH- deficient PHP1a patients, the hypothesis is that GH may also be of value in children with PHP1a who are GH-sufficient as well as in children with PPHP by accelerating growth velocity maximally prior to the cessation of growth secondary to early bone fusion. This study will examine the effects of GH on growth velocity in prepubertal GH-sufficient children with PHP1a and PPHP. Preliminary data for safety and dosing of GH, as well as quality of life effects will be gathered. If the results are promising, these children will be followed to final height after completion of this proposed initial investigation. This ultimately could lead to a new FDA-approved indication for GH use in all children with AHO, thus eliminating the need for GH testing for these children. The overall goal is to improve the quality of life in these patients.

描述（由申请人提供）： 奥尔布赖特遗传性骨营养不良（AHO）是一种罕见的遗传疾病，是由编码A链刺激基因蛋白（GS）的基因中的杂合失活突变引起的。 除其他异常外，它与身材矮小和肥胖有关。 由于组织特异性的印迹，在母体遗传等位基因上患有GNA突变的患者对多种G蛋白偶联激素具有抗性，这是一种称为pseudohypoparathyridist型1A型（PHP1A）的变体。 从父亲等位基因继承突变的患者具有相似的表型，但没有激素耐药性，称为假性甲状腺功能低下（PPHP）。 研究人员假设PHP1A患者对生长激素释放激素具有抵抗力，发现大约三分之二是生长激素（GH）缺乏。 GH疗法导致生长速度提高，成人高度高，BMI和肥胖降低以及脂质，骨密度，幸福感和自尊心的改善，没有GH使用的任何显着副作用。 但是，GH缺乏症并不是PHP1A中矮小的唯一原因。 在晚期骨龄体中反映的epiphyses的过早融合也是一个原因，并且发生在PHP1A和PPHP患者的PHP1A患者中。 体外和小鼠的研究暗示，在PHP1A和PPHP中，G蛋白的单倍症使可能是病因的软骨细胞分化会导致过早的软骨细胞分化。 基于GH缺乏PHP1A患者的GH试验的有希望的结果，假设是，GH在PHP1A的儿童中也可能具有GHP1A以及PPHP儿童的价值，并且通过在生长速度最大化生长速度之前加速了生长速度，从而降低了继发性生长速度到早期骨融合。 这项研究将检查GH对PHP1A和PPHP的青春期前GH充电儿童的生长速度的影响。 将收集有关GH的安全性和剂量的初步数据，以及生活质量效果。 如果结果是有希望的，则这些孩子将在完成此提议的初步调查后遵循到最终身高。 最终，这可能会导致所有患有AHO儿童的FDA批准的GH使用的新指示，从而消除了对这些儿童进行GH测试的需求。 总体目标是改善这些患者的生活质量。