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: 8032580
• 负责人: EMILY L GERMAIN-LEE
• 金额: $ 12.39万
• 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 2013-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032580
• 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) 是一种罕见的遗传性疾病，由编码刺激基因蛋白 (Gs) 链的基因杂合失活突变引起。 除其他异常外，它还与身材矮小和肥胖有关。 由于组织特异性印记，母系遗传等位基因上有 GNAS 突变的患者对多种 G 蛋白偶联激素具有抵抗力，这种变异被称为 1a 型假性甲状旁腺功能减退症 (PHP1a)。 遗传父系等位基因突变的患者具有相似的表型，但没有激素抵抗，称为假性甲状旁腺功能减退症（PPHP）。 研究人员假设 PHP1a 患者对生长激素释放激素有抵抗力，并发现大约三分之二的患者缺乏生长激素 (GH)。 GH 治疗可提高生长速度、提高成年身高、降低 BMI 和肥胖，并改善血脂、骨密度、幸福感和自尊，且没有任何因 GH 使用而产生的明显副作用。 然而，GH 缺乏并不是 PHP1a 身材矮小的唯一原因。 骨龄提前所反映的骨骺过早融合也是一个原因，这种情况发生在 GH 充足的 PHP1a 患者以及 PPHP 患者中。 体外和小鼠研究表明 PHP1a 和 PPHP 软骨细胞中 G 蛋白的单倍体不足导致软骨细胞过早分化，这可能是其病因。 基于 GH 试验在 GH 缺乏的 PHP1a 患者中取得的有希望的结果，我们假设 GH 也可能对 GH 充足的 PHP1a 儿童以及 PPHP 儿童有价值，因为它可以在出生前最大限度地加速生长速度。继发于早期骨融合的生长停止。 本研究将探讨 GH 对青春期前 GH 充足的 PHP1a 和 PPHP 儿童生长速度的影响。 将收集 GH 安全性和剂量以及生活质量影响的初步数据。 如果结果令人满意，在完成拟议的初步调查后，将跟踪这些儿童的最终身高。 这最终可能导致 FDA 批准在所有患有 AHO 的儿童中使用 GH 的新适应症，从而消除对这些儿童进行 GH 检测的需要。 总体目标是改善这些患者的生活质量。