Intranasal Delivery of Peptide Drugs to the Brain

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，影响大约十分之一的65岁以上人口。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（ß）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β生成的治疗尝试并不令人满意，因为它们直接针对β -或γ-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。因此，新的治疗方法可以抑制总β的产生，而不针对β或γ分泌酶的活性，这是非常有趣的。我们有一种不针对分泌酶的新技术，已经产生了一种潜在的肽候选药物P8，它能够在体外和AD的Tg小鼠模型中抑制β的产生，这种药物是稳定的，可以输送到大脑。我们现在正在开发P8作为一种新的多肽药物治疗阿尔茨海默病。重要的是，香草肽诱导的总ß和Aß40和42的减少不会改变或抑制ß或γ-分泌酶的活性。在SBIR期项目中进行的研究表明，P8可以通过鼻内和静脉给药两种方式进入大脑。在这个2期申请中，我们建议开展P8的临床前开发研究。研究将包括P8的特征，在临床前研究中支持P8鼻内给药的预制剂的开发，P8的药代动力学ADME评估以及P8的临床前药理学/疗效的开发。

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.