davunetide intranasal (AL-108) / Endo - LARVOL DELTA

Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG). (PubMed, Transl Psychiatry) - P2 | "These findings, while requiring caution due to the small cohort size, were linked with an apparent protection against brain cell death/disease progression by davunetide (AL-208) neuroprotective effects (neuron-specific enolase - NSE blood content). In men, also for the first time under these circumstances, neuroprotection was coupled to cognitive function increases in the treated group versus placebo, reaching healthy control levels in the Verbal Paired Associates II test, emphasizing the importance of sex-specific brain medicine."

Journal • Cardiovascular • CNS Disorders • Cognitive Disorders • Coronary Artery Disease • Ischemic stroke

The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis. (PubMed, J Mol Neurosci) - "In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP's ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization."

Journal • ADNP

Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity. (PubMed, Adv Drug Deliv Rev) - "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."

Journal • Review • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Davunetide promotes structural and functional recovery of the injured spinal cord by promoting autophagy. (PubMed, Neural Regen Res) - "These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms. This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury."

Journal • CNS Disorders • Inflammation • Orthopedics • TFEB

ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation. (PubMed, Mol Psychiatry) - "NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases."

Journal • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders • Movement Disorders • Progressive Supranuclear Palsy • ADNP

Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease. (PubMed, Transl Psychiatry) - P2 | "In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mood Disorders • Movement Disorders • Progressive Supranuclear Palsy • Psychiatry

Adnp/davunetide multi-site protection against tauoapthy (Neuroscience 2024) - "Modeling this by CRISPR-Cas9 editing in mice (Biol Psychiatry.2022;92:81), we showed protection by the ADNP fragment, investigational drug, davunetide (NAP)...Furthermore, analyzing clinical trial results, we discovered accelerated disease progression in women suffering from the pure tauopathy progressive supranuclear palsy (PSP), which was partly ameliorated by davunetide treatment (Transl Psychiatry. 2023;13:319) toward new research and development."

Alzheimer's Disease • CNS Disorders • Progressive Supranuclear Palsy • Psychiatry • ADNP • SIRT1

Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity. (PubMed, J Mol Neurosci) - "Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Mental Retardation • Psychiatry • ADNP

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice. (PubMed, Zool Res) - "Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • DLG4 • SYP

Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males. (PubMed, J Mol Neurosci) - "Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1-6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • Progressive Supranuclear Palsy • ADNP

Microtubule stabilising peptides: new paradigm towards management of neuronal disorders. (PubMed, RSC Med Chem) - "Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women. (PubMed, Transl Psychiatry) - "Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients."

Journal • CNS Disorders • Depression • Geriatric Disorders • Movement Disorders • Progressive Supranuclear Palsy • Psychiatry • Vascular Neurology

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms. (PubMed, Cells) - "Ketamine, used as a control, was ineffective, but both NAP and ketamine exhibited direct interactions with ADNP, as observed via in silico docking. (4) Through a microtubule-linked mechanism, NAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies. These novel findings explain previously published gene expression results and broaden NAP (davunetide) utilization in research and clinical development."

Journal • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • ADNP

Tau, ADNP, and sex. (PubMed, Cytoskeleton (Hoboken)) - "I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau-ADNP-NAP interactions were then explained with emphasis on sex and future translational medicine."

Journal

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development. (PubMed, Cells) - "However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer's, Parkinson's), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them."

Journal • Review • Alzheimer's Disease • Autism Spectrum Disorder • Cardiovascular • CNS Disorders • Depression • Developmental Disorders • Genetic Disorders • Mental Retardation • Movement Disorders • Parkinson's Disease • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Vascular Neurology • ADCYAP1 • IGF1

Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk. (PubMed, Cells) - "Reduced nuclear/cytoplasmic boundaries were observed in the p.Tyr718* ADNP-mutant line, with this malformation being corrected by the ADNP-derived fragment drug candidate NAP. (4) Distinct impairments characterize different ADNP mutants and reveal aberrant cytoplasmic-nuclear crosstalk."

Journal • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Rational Discovery of Microtubule-Stabilizing Peptides. (PubMed, J Chem Inf Model) - "FASTA sequences for ∼1000 peptides were crafted from single and double mutants of davunetide (NAP) and docked against the Taxol (TX) site on an octameric MT model representing a portion of the MT wall. Tryptophan quenching assays verified that P43 and P52 bind to nonpolymeric tubulin, whereas viability experiments on HEK cells confirmed their safety to pursue future pharmacological studies. The results herein presented are valuable to making progress in the rational design of MT-stabilizing peptides."

Journal • CNS Disorders

A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments. (PubMed, Mov Disord) - "Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology."

Journal • CNS Disorders • Dystonia • Movement Disorders • Parkinson's Disease • Progressive Supranuclear Palsy

A Novel Small Molecule, LCG-N25, Inhibits Oral Streptococcal Biofilm. (PubMed, Front Microbiol) - "Our previous study demonstrated that a repurposed natural compound napabucasin (NAP) showed good antimicrobial activity against oral streptococcal biofilms. We found that LCG-N25 exhibited a good antibacterial activity, low-cytotoxicity, and did not induce drug resistance of cariogenic S. mutans. These findings suggest that LCG-N25 may represent a promising antimicrobial agent that can be used as an adjuvant to the management of dental caries."

Journal • Dental Disorders • Infectious Disease

Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD). (PubMed, Life (Basel)) - "Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD."

Journal • Review • Chronic Kidney Disease • Diabetic Nephropathy • Nephrology • Renal Disease

Structure-based mimicking of hydroxylated biphenyl congeners (OHPCBs) for human transthyretin, an important enzyme of thyroid hormone system. (PubMed, J Mol Graph Model) - "Individual residues decomposition analysis confirms that Lys15, Leu17, Ala108, Ala109, Leu110, Ser117, and Thr119 of hTTR plays a major role in the binding of OHPCBs to form the lower energy hTTR-OHPCBs complexes. Molecular docking and simulations results emphasize that OHPCBs can efficiently bind at the active site of hTTR, which further leads to inhibition of transportation of T4 in human blood."

Journal

Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy. (PubMed, Prog Mol Biol Transl Sci) - "Clinical trials have suggested the potential efficacy of NAP (davunetide, CP201) for improving cognitive performance/functional activities of daily living in amnestic mild cognitive impairment (aMCI) and schizophrenia patients, respectively...We show that the peptide SKIP affects MT dynamics and MT-Tau association. Since MT impairment is linked with neurodegenerative and neurodevelopmental conditions, the current study implicates a paucity/dysregulation of MT-interacting endogenous proteins, like ADNP, as a contributing mechanism and provides hope for NAP and SKIP as MT-modulating drug candidates."

Journal • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Genetic Disorders • Immunology • Movement Disorders • Parkinson's Disease • Progressive Supranuclear Palsy • Psychiatry • Schizophrenia

Associations Between Amantadine Usage, Gait, and Cognition in PSP: A post-hoc Analysis of the Davunetide Trial. (PubMed, Front Neurol) - " This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes."

Journal • Retrospective data • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

The ADNP Syndrome and CP201 (NAP) Potential and Hope. (PubMed, Front Neurol) - "Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome."

Journal • Review • Autism Spectrum Disorder • Developmental Disorders • Genetic Disorders • Mental Retardation

[VIRTUAL] Correlations between amantadine usage, gait, and cognition in PSP: a post hoc analysis of the davunetide trial (MDS Congress 2020) - "This post hoc analysis of the davunetide trial dataset does not support the role of amantadine for symptomatic treatment of gait or cognition in PSP, but the trial was not powered to find such a difference. Also, the PSPRS does not include a measure of freezing of gait; this is relevant because some clinicians note freezing of gait responds to amantadine in a subset of PSP patients. Cognitive deficits strongly correlated over time with worsening of gait and balance in this population, but also with total PSPRS scores, likely reflective of overall disease progression."

Retrospective data • CNS Disorders • Cognitive Disorders