Intranasal Delivery of Peptide Drugs to the Brain

肽药物鼻内递送至大脑

• 批准号: 9455500
• 负责人: NAZNEEN N DEWJI
• 金额: $ 10万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9455500
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Brain; Canis familiaris; Cell Culture Techniques; Cell physiology; Clinical Pharmacology; Data; Development; Disease; Drug Kinetics; Elderly; Enzymes; Evaluation; Formulation; Goals; Human; In Vitro; Intranasal Administration; Intravenous; Manuscripts; Modification; Mus; N-terminal; Neurodegenerative Disorders; Pathologic; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Population; Preparation; Small Business Innovation Research Grant; Therapeutic; Transgenic Mice; Water; abeta accumulation; clinical development; drug candidate; gamma secretase; in vivo; interest; intravenous administration; nervous system disorder; neurotoxic; new technology; novel strategies; novel therapeutic intervention; peptide drug; pre-clinical; preclinical development; preclinical study; presenilin; presenilin-1; public health relevance; secretase

DESCRIPTION (provided by applicant): 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 γ-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 th ß- or the γ-secretase are therefore of great interest. We have 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 is stable and which can be delivered to the brain. We are now developing P8 as a new peptide drug for the treatment of AD. Importantly, Cenna's peptide-induced reductions of total Aß and Aß40 and 42, do not modify or inhibit either ß- or γ-secretase activities. Studies carried out in the Phase SBIR project showed that P8 can be delivered to the brain both, by intranasal and intravenous administration. In this Phase 2 application we propose to carry out studies for the pre-clinical development of P8. Studies will include the characterization of P8, the development of a pre-formulation to support intranasal delivery of P8 in pre-clinical studies, the pharmacokinetic ADME evaluation of P8 and the development of pre-clinical pharmacology/efficacy of P8.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性和致命的神经系统疾病，影响约十分之一的65岁以上的人口。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（AAPs）在脑中的形成和积累，AAPs被广泛认为是AD中的主要神经毒性剂。早期降低总腺苷酸产生的治疗尝试并不令人满意，因为它们直接靶向β-或γ-分泌酶的催化活性，这些酶已知水解其他底物以及APP，许多具有关键的细胞功能。因此，可以抑制总腺苷酸产生而不靶向β-或γ-分泌酶活性的新治疗方法引起了极大的兴趣。我们有一种不靶向分泌酶的新技术，它产生了一种潜在的肽类药物候选物P8，能够在体外和AD的Tg小鼠模型中抑制Ablast的产生，它是稳定的，可以被递送到大脑。我们现在正在开发P8作为治疗AD的新肽药物。重要的是，Cenna肽诱导的总A β 40和A β 42的减少不改变或抑制β-或γ-分泌酶活性。在SBIR阶段项目中进行的研究表明，P8可以通过鼻内和静脉内给药递送到大脑。在本II期申请中，我们计划开展P8临床前开发研究。研究将包括P8的表征、在临床前研究中支持P8鼻内给药的预制剂开发、P8的药代动力学ADME评价以及P8临床前药理学/疗效的开发。