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 -amyloid (A), widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total A production were unsatisfactory as they directly targeted the catalytic activities of - or ?-secretase, enzymes known to hydrolyze other substrates as well as APP, many with critical cellular functions. New therapeutic approaches that can inhibit total A production without targeting the activities of th - or the ?-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 A 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 A and A40 and 42, do not modify or inhibit either - or ?-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.
Alzheimer's disease (AD) 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 a small peptide, P8, that is active in vitro and in vivo in reducing the toxic species, A, into a new disease-modifying drug for the treatment of Alzheimer's Disease. In this application we will carry out the pre-clinical development of P8 as a potential disease-modifying drug for AD.
|Dewji, Nazneen N; Azar, Marc R; Hanson, Leah R et al. (2018) Pharmacokinetics in Rat of P8, a Peptide Drug Candidate for the Treatment of Alzheimer's Disease: Stability and Delivery to the Brain. J Alzheimers Dis Rep 2:169-179|
|Dewji, Nazneen N; Singer, S Jonathan; Masliah, Eliezer et al. (2015) Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce ß-amyloid in Alzheimer's disease. PLoS One 10:e0122451|