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.

阿尔茨海默病（AD）是一种进行性和致命的神经系统疾病，影响大约十分之一的65岁以上人群。目前还没有治愈这种疾病的方法。该疾病的病理特征包括ss-淀粉样蛋白（Ass）在大脑中的形成和积累，ss-淀粉样蛋白被广泛认为是AD的主要神经毒性物质。早期降低总Ass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，已知酶水解其他底物和APP，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，而不靶向ss-或s-的活性