Intranasal Delivery of Peptide Drugs to the Brain

描述(申请人提供)：多肽药物鼻腔给药到脑阿尔茨海默病(AD)是一种进行性和致命性的神经疾病，影响大约十分之一的65岁以上的人口。目前还没有治愈这种疾病的方法。该病的病理特征包括淀粉样蛋白(Ass)在大脑中的形成和积聚，该物质被广泛认为是AD的主要神经毒性物质。早期降低Ass总产量的治疗尝试并不令人满意，因为它们直接针对ss-或？-分泌酶的催化活性，这种酶可水解其他底物以及APP，其中许多具有关键的细胞功能。新的治疗方法可以抑制总ASS的产生，而不针对SS-或 因此，分泌酶引起了极大的兴趣。Cenna有一种不针对分泌酶的新技术，该技术已经产生了一个潜在的多肽候选药物P8，它在体外和在AD的TG小鼠模型中具有抑制Ass产生的能力，可能被开发为治疗AD的新多肽药物。开发治疗中枢神经系统疾病的候选多肽药物的一个重大挑战是，由于血脑屏障(BBB)的存在，将多肽系统地输送到中枢神经系统是不有效的，这对P8的发展至关重要。有证据表明，多肽的鼻腔给药是一种绕过血脑屏障的方法。直接鼻腔给药到大脑是一种非侵入性的替代方法，可以绕过血脑屏障，利用支配鼻道的嗅觉和三叉神经的通路。在这项应用中，我们建议探索通过鼻腔给药将P8输送到小鼠脑内。 与公共卫生相关：阿尔茨海默病是一种毁灭性的退行性神经疾病，影响65岁以上人口的十分之一。这种疾病没有治愈的办法。我们的总体目标是进一步开发一种8氨基酸多肽P8，它在体外和体内都具有活性，可以减少有毒物种Ass，成为治疗阿尔茨海默病的新的疾病修改药物。在此应用程序中，我们将探讨P8交付到 鼻腔给药对小鼠大脑的影响。

DESCRIPTION (provided by applicant): INTRANASAL DELIVERY OF PEPTIDE DRUGS TO THE BRAIN Alzheimer's disease (AD) is a progressive and fatal neurological disorder that affects approximately one-tenth of the population over the age of 65. There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of ss-amyloid (Ass), widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total Ass production were unsatisfactory as they directly targeted the catalytic activities of ss- or ¿-secretase, enzymes known to hydrolyze other substrates as well as APP, many with critical cellular functions. New therapeutic approaches that can inhibit total Ass production without targeting the activities of the ss- or the ¿-secretase are therefore of great interest. Cenna has a novel technology that does not target the secretases, which has yielded a potential peptide drug candidate, P8, with the ability to inhibit the production of Ass in vitro and in a Tg mouse model of AD, which could be developed as a new peptide drug for the treatment of AD. A significant challenge to the development of peptide drug candidates to treat disorders of the CNS, and critical to the development of P8, is that the systemic delivery of peptides to the CNS is not effective due to the presence of the blood brain barrier (BBB). There is evidence that intranasal delivery of peptides is a way to circumvent the BBB. Direct intranasal delivery of therapeutics to the brain is a non-invasive alternative to invasive delivery methods to by-pass the BBB, utilizing pathways along olfactory and trigeminal nerves innervating the nasal passages. In this application we propose to explore the delivery of P8 to the mouse brain by intranasal administration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a devastating degenerative neurological disorder that affects one-tenth of the population over the age of 65. There is no cure for the disease. Our overall goal is to further develop an 8-amino acid peptide, P8, that is active in vitro and in vivo in reducing the toxic species, Ass, into a new disease-modifying drug for the treatment of Alzheimer's Disease. In this application we will explore the delivery of P8 to the brains of mice by intranasal administration.