Intranasal Delivery of Peptide Drugs to the Brain

肽药物鼻内递送至大脑

• 批准号: 8394960
• 负责人: NAZNEEN N DEWJI
• 金额: $ 26.18万
• 依托单位: CENNA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394960
• 关键词: Affect; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein Precursor; Axonal Transport; Blood; Blood - brain barrier anatomy; Brain; Cell Culture Techniques; Cell physiology; Central Nervous System Diseases; Charge; Cleaved cell; Data; Development; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Elderly; Enzymes; Gastrointestinal tract structure; Goals; Human; In Vitro; Intracellular Transport; Intranasal Administration; Intravenous; Manuscripts; Methods; Modification; Molecular Conformation; Mus; N-terminal; Neural Pathways; Neurons; Nose; Olfactory Epithelium; Olfactory Nerve; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Plasma; Population; Preparation; Production; Proteins; Radiolabeled; Route; Specificity; Staging; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Trigeminal nerve structure; Water; Work; animal efficacy; base; drug candidate; extracellular; in vivo; interest; lipid solubility; molecular mass; mouse model; nervous system disorder; neurotoxic; new technology; novel strategies; novel therapeutic intervention; presenilin; presenilin-1; prevent; radiotracer; secretase; sound; uptake

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.

描述（由申请人提供）：向大脑鼻内输送肽类药物阿尔茨海默氏病 (AD) 是一种进行性、致命性神经系统疾病，影响大约十分之一的 65 岁以上人口。目前尚无治愈该疾病的方法该疾病的病理特征包括大脑中 ss-淀粉样蛋白 (Ass) 的形成和积累，广泛认为它是 AD 早期治疗尝试的主要神经毒剂。在降低总 Ass 产量方面的效果并不令人满意，因为它们直接针对 ss- 或 ¿ -分泌酶，已知能水解其他底物以及 APP 的酶，许多具有关键的细胞功能，可以抑制总 Ass 的产生，而不针对 ss- 或 ss- 的活性。 ¿因此，Cenna 拥有一种不针对分泌酶的新技术，该技术产生了一种潜在的肽药物候选物 P8，能够在体外和 AD 的 Tg 小鼠模型中抑制 Ass 的产生。 ，它可以开发为治疗 AD 的新肽药物，开发治疗中枢神经系统疾病的候选肽药物的一个重大挑战，并且对 P8 的开发至关重要，是将肽全身递送至 AD。中枢神经系统由于血脑屏障 (BBB) 的存在而无效 有证据表明，鼻内递送肽是一种绕过 BBB 的方法，直接鼻内递送治疗剂至大脑是侵入性递送方法的一种非侵入性替代方法。利用沿着支配鼻道的嗅觉和三叉神经的通路绕过血脑屏障。在本申请中，我们建议探索通过鼻内给药将 P8 递送至小鼠大脑。 公共健康相关性：阿尔茨海默病是一种毁灭性的退行性神经系统疾病，影响十分之一的 65 岁以上人口。我们的总体目标是进一步开发一种 8 氨基酸肽 P8，它在体外和体内都具有活性，可将有毒物质 Ass 减少为治疗阿尔茨海默病的新疾病缓解药物。在本应用中，我们将探索将 P8 递送至体内。 通过鼻内给药进入小鼠大脑。