title: NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP).
abstract: Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. igozes@post.tau.ac.il
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Morimoto
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tiong
authors.forename: Anthony
authors.initials: A
authors.lastname: Fox
authors.forename: Karole
authors.initials: K
authors.lastname: Sutherland
authors.forename: David
authors.initials: D
authors.lastname: Dangoor
authors.forename: Miriam
authors.initials: M
authors.lastname: Holser-Cochav
authors.forename: Karin
authors.initials: K
authors.lastname: Vered
authors.forename: Paul
authors.initials: P
authors.lastname: Newton
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Christopher H
authors.initials: CH
authors.lastname: van Dyck
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats
chemical_list: D018696:Neuroprotective Agents; D009842:Oligopeptides; C425904:davunetide