Nasal Leptin - Polymer Conjugate for Treatment of Obesity

 描述（由申请人提供）：尽管他们患严重疾病（包括冠心病、2型糖尿病、高血压、某些类型的癌症和中风）的风险增加，但超重或肥胖个体的公共卫生危机仍有增无减。安全性问题阻碍了旨在控制体重的药物的开发，目前在美国市场上销售的四种药物都有副作用，要么限制了它们对非常肥胖者的使用，要么阻止它们在患者中获得广泛接受。开发安全有效且无不良副作用的新减肥药物仍然是一个重要的公共卫生目标。瘦素是一种由白色脂肪细胞分泌的激素，通过调节饥饿感和调节能量消耗来调节体内储存的脂肪量。虽然安进公司没有成功地获得重组人瘦素作为肥胖症（BMI 27-37）治疗的监管批准，但他们的研究和许多其他人的研究已经产生了大量关于这一结果原因的信息。压倒性的证据表明，由于肥胖患者出现瘦素抵抗现象，特别是那些BMI处于量表上端的患者，该激素的临床试验失败了。基于脑脊髓液和血清瘦素水平的计算模型表明，在肥胖个体中（BMI>30，瘦素水平约为40 ng/ml），激素无法穿过血脑屏障（BBB）几乎占这种阻力的三分之二。预计一种能够到达大脑受体的瘦素形式将是超重和轻度肥胖的有效治疗方法，这占2型糖尿病风险的大多数。在筛板处鼻内施用瘦素，称为鼻内至脑（INB）递送，使得瘦素能够进入脑而不暴露于血浆蛋白酶或被BBB排除。NeuroNano Pharma，Inc.正在开发一种新的人瘦素制剂（“hu-leptiPOL-N”），其中泊洛沙姆P85的单一聚合物链共价连接到蛋白质的N-末端。在初步研究中，与天然瘦素相比，具有随机连接蛋白质的游离氨基之一的单一P85链的密切相关的鼠瘦素类似物表现出较低的活性（约14倍），但在INB给药后显示出显著的脑下丘脑摄取能力（约为天然瘦素的4倍）。我们建议优化泊洛沙姆修饰以产生更有活性的hu-leptiPOL-N，在INB给药后，其将表现出更大的受体活化，同时保留其性质。 大脑（和大脑下丘脑）的摄取。总体目标是提供临床前证据，证明鼻内给药的hu-leptiPOL-N可有效治疗饮食诱导的肥胖（DIO）小鼠模型中的超重和肥胖。如果优化的hu-leptiPOL-N在脑下丘脑递送和DIO小鼠的喂养研究中表现出优于天然瘦素，我们将启动开发计划，最终以IND开始临床研究。

 DESCRIPTION (provided by applicant): Despite their increased risk of developing serious diseases including coronary heart disease, Type 2 diabetes, hypertension, certain types of cancers, and stroke, the public health crisis of individuals who are overweight or obese continues unabated. Safety issues have hampered development of drugs designed to control weight, and the four drugs currently on the market in the U.S. each has side effects that either limits their use to the very obese or prevents them from gaining wide acceptance in patients. Development of new weight loss drugs that are safe and effective with no undesirable side effects remains an important public health goal. Leptin is a hormone secreted by white adipocytes and regulates the amount of fat stored in the body by adjusting both the sensation of hunger and by adjusting energy expenditures. While Amgen did not succeed in its efforts to gain regulatory approval of recombinant human leptin as a treatment for obesity (BMI 27-37), their studies and those of many others since have yielded a wealth of information regarding the reasons for this outcome. Overwhelming evidence suggests that clinical trials with the hormone failed due to the phenomenon of leptin resistance appearing in obese patients, especially those with BMIs at the upper end of the scale. Computational modeling based on cerebrospinal fluid and serum levels of leptin indicates that in obese individuals (BMI>30, leptin levels of about 40 ng/ml), the inability of the hormone to cross the blood-brain barrier (BBB) accounts for almost two-thirds of this resistance. It is expected that a form of leptin capable of reaching its receptos in the brain would be an effective therapy for the overweight and mildly obese, which accounts for the majority of those at risk for type 2 diabetes. Intranasal administration of leptin at the cribriform plate, known as intranasal-to-brain (INB) delivery, enables leptin to enter the brain without exposure to plasma proteases or exclusion by the BBB. NeuroNano Pharma, Inc. is developing a novel formulation of human leptin ("hu-leptiPOL-N") in which a single polymer chain of the poloxamer, Pluronic(r) P85, is covalently attached to the N-terminus of the protein. In preliminary studies, a closely related murine leptin analog with a single P85 chain randomly attached one of the free amino groups of the protein exhibited lower activity (~14-fold) as compared to native leptin but displayed a remarkable ability for uptake in brain hypothalamus following INB administration (about 4 times higher than that observed with native leptin). We propose to optimize the poloxamer modification to produce a more active hu-leptiPOL-N that, following INB administration, will exhibit greater receptor activation while retaining the property of uptake in the brain (and brain hypothalamus). The overall goal is to provide preclinical evidence that hu-leptiPOL-N, administered intranasally, is effective in treating overweight and obesity in the diet-induced obese (DIO) mouse model. If the optimized hu-leptiPOL-N demonstrates superiority to native leptin in brain hypothalamic delivery and in feeding studies in DIO mice, we will initiate a development plan to culminate in an IND to commence clinical studies.