Intranasal Delivery of Peptide Drugs to the Brain

描述（由申请方提供）：肽类药物经鼻递送至大脑阿尔茨海默病（AD）是一种进行性和致死性神经系统疾病，影响约十分之一的65岁以上人群。目前没有治愈这种疾病的方法。该疾病的病理学特征包括β-淀粉样蛋白（Ass）在脑中的形成和积累，其被广泛认为是AD中的主要神经毒性剂。早期降低总Ass产生的治疗尝试是不令人满意的，因为它们直接靶向β-或ω-分泌酶的催化活性，已知这些酶水解其他底物以及APP，许多具有关键的细胞功能。新的治疗方法可以抑制总的Ass产生，而不靶向ss-或 因此，分泌酶引起了极大的兴趣。Cenna拥有一种不靶向分泌酶的新技术，该技术已经产生了一种潜在的肽药物候选物P8，该候选物具有在体外和AD的Tg小鼠模型中抑制Ass产生的能力，其可以被开发为用于治疗AD的新肽药物。开发治疗CNS病症的肽药物候选物的重大挑战，以及对P8的开发至关重要，是由于血脑屏障（BBB）的存在，肽向CNS的全身递送是无效的。有证据表明，鼻内递送肽是一种绕过BBB的方法。将治疗剂直接鼻内递送至脑是侵入性递送方法的非侵入性替代方案，以利用沿支配鼻通道的沿着嗅神经和三叉神经的通路绕过BBB。在本申请中，我们提出探索通过鼻内给药将P8递送至小鼠脑。 公共卫生相关性：阿尔茨海默病是一种破坏性的退行性神经系统疾病，影响65岁以上人口的十分之一。这种病无药可治。我们的总体目标是进一步开发一种8-氨基酸肽P8，其在体外和体内都具有减少毒性物质Ass的活性，成为一种用于治疗阿尔茨海默病的新的疾病修饰药物。在这个应用程序中，我们将探讨P8的交付， 通过鼻内给药对小鼠的脑进行了研究。

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.