Long-acting ghrelin for the treatment of cancer cachexia

项目摘要 恶病质是一种复杂的综合征，其特征是非自愿的体重减轻和骨骼肌萎缩。 会导致疲劳、虚弱和食欲不振，而增加卡路里摄入量并不能扭转这种情况。更多 超过一半的癌症患者会患恶病质，超过20%的癌症死亡是由恶病质引起的。 与恶病质相关的许多并发症包括对药物治疗的反应受损，以及 感染机会增加，预后不良，生活质量下降。目前，没有FDA- 已被批准用于癌症恶病质的治疗，但激素Ghrelin最近成为一种与 潜力巨大。在动物和人类身上进行的几项研究表明，胃促生长素增加了食物的摄入量， 刺激生长激素的释放，增加肌肉质量，减少炎症的标志。 然而，由于以下几个原因，ghrelin作为一种治疗方法的使用受到限制：1)ghrelin必须服用2-3次。 每天观察疗效，因为它的半衰期很短，只有30分钟；2)Ghrelin脱乙酰化为非活性形式 在不到5分钟内发生；以及3)目前静脉注射Ghrelin以观察治疗效果。这个 在SBIR第一阶段完成的研究解决了这些问题，产生了一种长效Ghrelin衍生物 它可以每隔一天在大鼠皮下注射一次，以逆转恶病质对小鼠的影响 吉田大鼠模型。在这项第二阶段申请中提出的研究将调查我们长期- 在另外两个模型中使用Ghrelin改善恶病质。长效环鸟苷生产方法的研究 Ghrelin将到位。我们将使用IND-Enabling GLP毒性和免疫原性研究 CGMP材料。在开始人体试验之前，这些研究是必要的。一旦完全开发，这个长长的- 代理Ghrelin衍生物将提供一种患者友好的恶病质治疗方法，将显著改善 癌症患者以及其他慢性疾病患者的预后和生活质量 充血性心力衰竭(CHF)和慢性阻塞性肺疾病(COPD)。

Project Summary Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 20% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cancer cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake, stimulates the release of growth hormone, increases muscle mass, and reduces markers of inflammation. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 30 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies completed during SBIR Phase I address each of these issues, resulting a long-acting ghrelin derivative that could be dosed subcutaneously once every other day in rats to reverse the effects of cachexia in the Yoshida rat model. The studies proposed in this Phase II application will investigate the ability of our long- acting ghrelin to ameliorate cachexia in two additional models. Methods for cGMP production of the long-acting ghrelin will be put in place. We will perform IND-enabling GLP toxicity and immunogenicity studies using the cGMP material. These studies are needed prior to beginning human trials. Once fully developed, this long- acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patients with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).