ADNP-derived peptide · tau research
Davunetide, also called NAP or AL-108, is an eight-amino-acid peptide (NAPVSIPQ) taken from activity-dependent neuroprotective protein (ADNP), a protein essential for brain formation. It was studied as a nasal spray in mild cognitive impairment, schizophrenia and the tau disease progressive supranuclear palsy, failed its largest trial, and has not been approved1,4.
In cell and animal studies, NAP appears to stabilize microtubules, the protein filaments that hold a nerve cell's shape and structure. Tau normally helps protect microtubules; when tau levels are reduced, NAP was shown to shield microtubules from the severing enzyme katanin1. Other laboratory work linked it to activation of the PI3K/Akt and MAPK/MEK1 survival pathways and to fewer dying neurons in brain tissue1. Preclinical studies also reported less tau phosphorylation, the chemical change that accumulates in tau-driven diseases such as progressive supranuclear palsy4. None of these mechanisms has been shown to produce clinical benefit in people.
Human data come from a few small-to-mid-sized trials of the nasal spray. In 144 people with amnestic mild cognitive impairment, a 12-week trial missed its composite memory endpoint, with possible signals on two individual tasks2. In 63 people with schizophrenia, it did not improve the main cognition battery versus placebo, though one functional-capacity measure favored it3. The largest study, a 52-week phase 2/3 trial in 313 people with progressive supranuclear palsy, found no difference from placebo on either primary measure, and the authors concluded it is not an effective treatment for that disease4. That trial completed in 2012, and no later davunetide study is registered on ClinicalTrials.gov5. Most of the encouraging findings remain in cells and animals1.
Davunetide is not approved by the FDA, and we found no approval by any other regulator; its registered human trials all completed by 20125.
In trials it was generally well tolerated2,3. In the supranuclear palsy trial, nasal effects were more common than with placebo: nosebleeds (12% versus 8%), runny nose (10% versus 5%) and nasal discomfort (10% versus under 1%). Serious adverse events and deaths were similar between groups4. Long-term effects are unknown, and there are no human data outside these trials.
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