Addressing Alzheimers Disease Tangles: From NAP to AL-108

Abstract

AL-108 is the intranasal formulation of NAP (a peptide of eight amino acids, NAPVSIPQ). Phase IIa clinical results have recently shown that AL-108 has a positive impact on memory function in patients with amnestic mild cognitive impairment (aMCI), a precursor to Alzheimer's disease (AD). The clinical development of AL-108 has been based on extensive studies showing pre-clinical efficacy for NAP. NAP has demonstrated potent neuroprotective activity in vitro and in vivo. Its mechanism of action is thought to center on the modulation of microtubule stability in the face of outside damage. Such an effect on structures of such central importance in a broad range of cellular functions is thought to explain NAP's activity in wide ranging models of cellular damage and neurodegeneration. The following article reviews NAP's discovery and pharmacological characterization that has led to clinical development of a novel tangle-directed drug candidate.

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

“…In spinal cord injury and optic nerve crush models, local administration of paclitaxel improves axonal regeneration and motor function (Hellal et al, 2011;Sengottuvel et al, 2011). In addition, NAP, a peptide with possible indirect MT-stabilizing activity (Yenjerla et al, 2010), has pathological and behavioral benefits in several tauopathy models (Gozes et al, 2009). NAP is in Phase II clinical trials for tauopathy.…”

The Future for Dementia Research: a Perspective from the Journal of Molecular Neuroscience

“…A further difference is that the current study is targeting a prodromal or very mildly affected population, showing a slowing of clinical decline as measured by the Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores, paralleling amyloid clearance. Indeed, other investigational drugs showed cognitive protection in this population (e.g., (Gozes et al 2009;Ayton et al 2013;Morimoto et al 2013)). The impact of tauopathy, a major hallmark of Alzheimer's disease and other neurodegeneration (Pachima et al 2016), is not directly addressed in the most recent study.…”

VIP–PACAP 2010: My Own Perspective on Modulation of Cognitive and Emotional Behavior

“…This editorial focuses on cognitive and emotional behavior in relation to vasoactive intestinal peptide (VIP; Said and Mutt 1972), pituitary adenylate cyclase activating polypeptide (PACAP; Arimura 1992), and our original discovery of the VIP-regulated activity-dependent neuroprotective protein (ADNP) and its peptide derivative, drug candidate NAP (NAPVISPQ, generic name davunetide; Bassan et al 1999;Gozes et al 2009). …”

“…The above studies have been translated into human clinical trials (Allon Therapeutic Inc.) demonstrating that NAP (generic name, davunetide; Gozes et al 2009) improves cognitive scores in a patient population suffering from amnestic mild cognitive impairment (Markesbery et al 2006;Petersen et al 2006) that has been associated with tauopathy (Schmechel et al 2008;Gozes et al 2009); NAP (davunetide) also improved functional capacity in schizophrenia patients (Javitt 2010) and is being developed for treatment of the tauopathy, progressive supranuclear palsy.…”

“…This selective review on VIP-PACAP-ADNP-NAP that highlights the current issue of the Journal of Molecular Neuroscience paves the path to new and original research. Our additional comprehensive reviews are accessible for perspective reading (Gozes 2007(Gozes , 2008Gozes 2010;Gozes et al 2005;Gozes et al 2009). New and exciting findings will be presented at the forthcoming VIP-PACAP and related peptides meeting in Eilat, Israel, 2011.…”