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Review
. 2025 May:220:115573.
doi: 10.1016/j.addr.2025.115573. Epub 2025 Apr 2.

Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity

Artur Galushkin  1 , Illana Gozes  2
Affiliations
Free article
Review

Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity

Artur Galushkin et al. Adv Drug Deliv Rev. 2025 May.
Free article

Abstract

In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in the context of neurodevelopmental and neurodegenerative disorders. ADNP, a protein essential for brain development and function, is associated with tauopathy-related diseases, such as Alzheimer's Disease (AD), and circadian rhythm regulation. NAP enhances microtubule stability and prevents tauopathy. In preclinical studies, NAP shows promise in improving cognitive performance and correcting behavioral deficits in different models. Clinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, and potential efficacy in improving cognitive function, making it a viable therapeutic option. In the pure tauopathy, progressive supranuclear palsy, NAP (davunetide) significantly slowed disease progression in women in a phase II-III clinical trial. Additionally, the complex interactions between ADNP, associated pathways, and circadian regulation and the extensive NAP compensation upon ADNP deficiency attest to further clinical development. Thus, NAP is an example of a reductionist approach in drug delivery, replacing/enhancing the critical large ADNP-related pathways including dysregulated microtubules and tauopathy with a small brain bioavailable investigational drug, davunetide.

Keywords: Activity-dependent neuroprotective protein (ADNP); Alzheimer’s disease; Brain delivery; Circadian clock; NAP (davunetide); Tauopathy.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Professor Gozes is a named inventor on multiple patents, and patent applications for davunetide/ADNP use serving as VP Drug Development at ExoNavis Therapeutics Ltd, holding a license for davunetide clinical development. The company initially targets progressive supranuclear palsy (PSP) and the ADNP syndrome with davunetide with Orphan Drug Designation #DRU-2017–6243, and Pediatric Rare Disease Designation by the US Food and Drug Administration (FDA) as well as Orphan Medicinal Product Designation by the European Medicines Agency (EMA).].

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