EFFECTS OF SOMATOKINE IN MYOTONIC DYSTROPHY TYPE 1

这些1期研究检验了一种可能的治疗强直性肌营养不良1型(DM1)的新方法，DM1是成人肌营养不良最常见的形式。目前还没有治疗方法来扭转其逐渐消瘦和虚弱的趋势。低水平的睾酮和生长激素，以及胰岛素抵抗，似乎是肌肉丧失的原因，但逆转这些激素异常的治疗试验未能产生显著改善。之前的胰岛素样生长因子-1[IGF1]试验提供了希望。在7名患者中，rhlGF1治疗增加了强度、蛋白质合成和胰岛素作用，但副作用导致2名患者退出。一种新的、耐受性更好、作用时间更长的rhlGF1制剂现已从Insmed公司获得。在与重组人IGF结合蛋白3的复合体中，它是SomatoKine，rhlGF1，它将在本提案中使用。初步研究表明，在健康成年人、糖尿病患者和髋部骨折后接受治疗的老年妇女中，它是安全和耐受性良好的。我们将在DM1中评估SomatoKine。这项建议的目的是评估每天皮下注射生长因子治疗肌肉萎缩和无力的安全性和可行性，每项研究涉及15名DM1患者：1)最初24周的生长因子[0.5、1.0和2.0 mg/kg，每天给药8周]的剂量递增研究，以根据在每个剂量下观察到的副作用、药物水平和疗效[双能X射线吸收法(DEXA)；定量肌力测定；手动肌肉力量测试]来确定“最佳剂量”；2) 随后对SomatoKine进行了一项为期24周的研究，使用“最佳剂量”来证明其作为为期6个月的每日治疗的安全性和可行性。此外，我们将通过测量针状肌肉活检样本中p70S6K的磷酸化来寻找IGF1细胞内信号改变的证据。这些样本来自为期24周的“最佳剂量”SomatoKine研究中的10名DM1患者和10名年龄性别匹配的正常志愿者，他们将只接受SomatoKine两天的治疗。标本将在“最佳剂量”治疗前和治疗两天后从股外侧肌获得。这些研究将检验我们的假设，即IGF1的超生理水平是安全和耐受性良好的，并提供关于疗效的初步数据(逆转肌肉萎缩和虚弱)。如果这个项目的结果是 证明是有希望的，我们计划进行一个更大的，多中心，2期，SomatoKine对照试验。

These phase 1 studies examine a possible new treatment for myotonic dystrophy type1 (DM1), the most common form of adult muscular dystrophy. At present no treatment exists to reverse its progressive wasting and weakness. Low levels of testosterone and growth hormone, as well as insulin resistance, appear to contribute to the muscle loss, but therapeutic trials to reverse these hormonal abnormalities have failed to produce significant improvement. A previous trial of insulin-like growth factor-1 [IGF1] has offered promise. Treatment with rhlGF1 increased strength, protein synthesis, and insulin action in 7 patients but side effects caused 2 to drop out. A new, better tolerated, longer acting, preparation of rhlGF1, is now available from INSMED. It is SomatoKine, rhlGF1 in complex with recombinant human IGF binding protein 3, and it will be used in this proposal. Preliminary studies show it is safe and well tolerated in healthy adults, diabetics, and older women treated after hip fracture. We will evaluate SomatoKine in DM1. The aim of this proposal is to evaluate the safety and feasibility of daily subcutaneous injections of SomatoKine for treatment of muscle wasting and weakness by performing two sequential studies, each involving 15 patients with DM1: 1st) An initial 24-Week Dose Escalation Study of SomatoKine [0.5, 1.0, and 2.0 mg/kg, with each dose given daily for 8 weeks] to identify an "optimal dose" based upon the side effects, drug levels, and efficacy [dual energy x-ray absorptiometry (DEXA); quantitative myometry; manual muscle strength testing] observed at each dose; 2nd) A subsequent 24-Week study of SomatoKine using an "Optimal Dose" to demonstrate its safety and feasibility as a daily treatment for a six month period. In addition, we will search for evidence of altered signaling along the intracellular pathway for IGF1 by measuring phosphorylation of p70S6K in needle muscle biopsy specimens obtained from 10 DM1 patients in the 24-Week "Optimal Dose" SomatoKine Study and from 10 age-gender matched normal volunteers who will receive SomatoKine for only two days. Specimens will be obtained from vastus lateralis muscle before and after two days of "optimal dose" treatment. These studies will test our hypothesis that supraphysiologic levels of IGF1 are safe and well tolerated and provide preliminary data regarding efficacy (reversal of muscle wasting and weakness.) If the results of this project prove promising, we plan to carry out a larger, multi-center, phase 2, controlled trial of SomatoKine.