NAP
Davunetide.

NAP / Davunetide: A Breakthrough in Neuroprotective Therapy

Discovering NAP: The Work of Professor Illana Gozes

NAP (NAPVSIPQ) is a small peptide derived from the Activity-Dependent Neuroprotective Protein (ADNP), a crucial protein in brain development and function. This remarkable discovery is credited to Professor Illana Gozes, a pioneer in the field of neurobiology. Her groundbreaking research revealed that NAP plays a vital role in stabilizing microtubules, the structural components essential for maintaining cell shape, growth, and intracellular transport, particularly in neurons.

The Mechanism of Action: How NAP Works

NAP’s ability to stabilize microtubules underpins its neuroprotective effects. Microtubules are critical for the proper functioning of neurons, especially in transporting nutrients and signaling molecules throughout the cell. In many neurodegenerative diseases, microtubule dysfunction leads to neuronal damage and cell death. NAP helps to prevent this by binding to microtubules and preserving their structure and function, thereby protecting neurons from degeneration.

Therapeutic Potential: Davunetide in Clinical Trials

Davunetide, the drug formulation of NAP, has shown promising results in clinical trials for various neurodegenerative conditions. Notably, it has been tested in patients with Progressive Supranuclear Palsy (PSP) and Mild Cognitive Impairment (MCI), conditions for which there are currently no effective treatments.

In these trials, Davunetide demonstrated the ability to slow the progression of symptoms, suggesting that it could offer a new therapeutic option for patients suffering from these debilitating conditions. Although further research is needed to fully establish its efficacy, the potential of Davunetide to address unmet medical needs in neurodegeneration is significant.

Broad Implications: Beyond PSP and MCI

The implications of NAP extend beyond its current applications. Given its foundational role in neuronal protection, there is strong potential for its use in treating a broader range of neurodevelopmental and neurodegenerative diseases, including ADNP Syndrome (Shortly commencing Phase 3 clinical trials), Alzheimer’s Disease, Parkinson’s Disease, and other tauopathies. The ongoing research and development efforts aim to explore these possibilities further, potentially leading to new and innovative treatments for patients worldwide.

Davunetide’s Uniqueness

Davunetide is an intranasal investigational product, administered using a multi-dispensing, metered nasal spray pump device containing an aqueous solution.

Davunetide crosses the BBB and has beneficial effects on synaptic development by promoting:

• Neuronal cell survival
• Synaptic maturation
• Synaptic plasticity
• Axonal transport
• Peripheral activities include: 

• 1. Muscle protection
  2. Skin regulation
  3. wound healing
  4. Anti-inflammatory effects
  5. Regulation of the microbiome

The cumulative human subject exposure to Davunetide from about 10 clinical studies in which it was administered either intranasally or intravenously is 564.

Davunetide is the generic name for the investigational drug, also known as NAP, NAP peptide or NAPVSIPQ. It is designed to be applied intranasally (AL-108) with doses specifically adapted for the treated individuals.

The mechanism of action of Davunetide is through its interaction with the cellular skeleton (cytoskeleton) with major building blocks microtubules – providing cell structure and function

• NAPVSIPQ Interact with the microtubule end binding proteins (EB1 and EB3). Davunetide enhances ADNP-EB1/EB3 interaction.
• NAPVSIPQ interacts with proteins containing SH3 domains essential for cytoskeletal function
• NAPVSIPQ binds the armadillo domain of beta catenin important for WNT signaling critical for development
• NAPVSIPQ also enters the cell nucleus interacting with an ADNP zinc finger, providing protection against ADNP transcriptional dysregulation.

• ADNP-deficiency exhibits Alzheimer’s-like Tau pathology (tauopathy). The mechanism of tauopathy involved dissociation of Tau from the microtubules, for example through the accumulation of excess of zinc ions.

• Tau binds EB1/EB3, which enhances Tau-microtubule interaction, protecting again tauopathy. The binding of Davunetide and EB1/EB3 results in a dramatic increase in the Tau-microtubule interaction, leading to neuronal plasticity/ brain protection.

• By increasing neuronal plasticity, Davunetide promotes formation of mature dendritic spines (post- synapse) and enhances microtubule invasion to the tip of the growth cone (pre-synapse). Davunetide protects the cell scaffold and transport system by promoting neurite outgrowth, preventing axonal transport deficits and increasing microtubule dynamics. This explains the breadth and efficiency of Davunetide’s neuroprotective capability along with its neurotrophic capacities.

The Future of Neuroprotection

Professor Illana Gozes’ discovery of NAP has opened a new frontier in neuroprotective therapies. As research continues, the promise of Davunetide as a treatment for neurodegenerative diseases grows stronger. At ExoNavis Therapeutics, we are committed to advancing this groundbreaking work and bringing new hope to patients and their families.