The ADNP Syndrome and CP201 (NAP) Potential and Hope

Gozes, Illana

doi:10.3389/fneur.2020.608444

Cited by 34 publications

(32 citation statements)

References 52 publications

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“…Most drugs targeting microtubules are anticancer agents that may also possess anti-neurodegenerative and antiviral effects ( Hung and Fu, 2017 ; Fernandez-Valenzuela et al., 2020 ; Tsai et al., 2020 ; Sirakanyan et al., 2021 ). Many of these drugs demonstrated beneficial effects in animal models, however those tested in humans are few and include TPI-287 and NAP (Davunetide CP201), an intranasal neuropeptide (NAPVSIPQ)(NAP) (NCT01966666) ( Gozes, 2020 ). These MSAs have not reached the clinic, however, activity-dependent neuroprotective protein (ADNP), derived from NAP, remains a potential hope and is scheduled for future clinical trials ( Varidaki et al., 2018 ; Al-Horani and Kar, 2020 ; Santiago-Mujika et al., 2021 ).…”

Section: Treatment Strategies For Pathological Cell-cell Fusionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Treatment Strategies For Pathological Cell-cell Fusionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…In conclusion, PACAP and NAP play a key role in retinal physiopathology; however, while PACAP's half-life is a minute or shorter, NAP's half-life is relatively long for a peptide, half an hour. NAP has previously been used in clinical trials showing safety and tolerability as well as efficacy increasing cognitive functions and protecting activities of daily living in mild cognitive impairment patients and schizophrenia patients, respectively (Gozes 2020). Overall, the evidences reported suggest that PACAP and NAP could be considered good candidates for therapeutic approach to DR. cell-specific markers in ischemia-induced retinal degeneration.…”

Section: Discussionmentioning

confidence: 96%

“…The protective action of NAP was demonstrated in many in vitro and in vivo studies; it prevents apoptotic cell death in neurons exposed to different kinds of stress such as glucose deprivation and β-amyloid or tetrodotoxin treatment, and in a rat model of cerebral ischemia and severe head injury (Bassan et al 1999;Leker et al 2002;Beni-Adani et al 2001;Zaltzman et al 2005;Zemlyak et al 2007;Jehle et al 2008;Gozes et al 2008;Belokopytov et al 2011). Noteworthy, the chemical structure of this small fragment peptide allows it to penetrate into cell membrane and by binding to microtubules it protects astrocytes and neurons (Divinski et al 2004;Oz et al 2012;Ivashko-Pachima et al 2017;2019a and2019b;2020;Gozes et al 2015;Grigg et al 2020). Furthermore, it has been demonstrated that NAP provides significant neuroprotection also in a diabetes rat model (Idan-Feldman et al 2011) and it has been also showed that NAP regulates PAC1 expression (Kapitansky et al 2020).…”

Section: Introductionmentioning

confidence: 99%

PACAP and NAP: Effect of Two Functionally Related Peptides in Diabetic Retinopathy

et al. 2021

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptide involved in physio-pathological processes of the eye. It exerts multiple effects directly through activation of its related receptors and indirectly through increases in the synthesis of activity-dependent neuroprotective protein (ADNP). To study the role of ADNP and protect against ADNP deficiencies, a small peptide called NAP was synthetized. It includes an eight amino acid active site sequence of ADNP. In this review, we summarize the knowledge regarding the neuroprotective function played by PACAP and NAP in retinal tissue and provide an overview of the correlation between PACAP and ADNP in the context of diabetic retinopathy.

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“…Indeed, some of the first concerns regarding the complex interaction between genotype and the conducting laboratory were raised in the field of rodent behavioral phenotyping (Crabbe et al 1999). While mouse and rat models may predict the human situation, such as the case of activity-dependent neuroprotective protein (ADNP) and the potential of its fragment as a drug (reviewed in Gozes, 2020), the utility of any findings critically depends on their replicability in other laboratories (Kafkafi et al, 2018; Voelkl et al, 2018). A similar concern arises regarding the interaction between the conducting laboratory and novel pharmacological treatments (e.g., Rossello et al, 2019) that are of vital importance for translational research, leading to novel drug developments.…”

Section: Introductionmentioning

confidence: 99%

Improving replicability using interaction with laboratories: a multi-lab experimental assessment

Jaljuli

Kafkafi

Giladi

et al. 2021

Preprint

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Phenotyping inbred and genetically-engineered mouse lines has become a central strategy for discovering mammalian gene function and evaluating pharmacological treatment. Yet the utility of any findings critically depends on their replicability in other laboratories. In previous publications we proposed a statistical approach for estimating the inter-laboratory replicability of novel discoveries in a single laboratory, and demonstrated that previous phenotyping results from multi-lab databases can be used to derive a Genotype-by-Lab (GxL) adjustment factor to ensure the replicability of single-lab results, for similarly measured phenotypes, even before making the effort of replicating the new finding in additional laboratories. The demonstration above, however, still raised several important questions that could only be answered by an additional large-scale prospective experiment: Does GxL-adjustment works in single-lab experiments that were not intended to be standardized across laboratories? With genotypes that were not included in the previous experiments? And can it be used to adjust the results of pharmacological treatment experiments? We replicated results from five studies in the Mouse Phenome Database (MPD), in three behavioral tests, across three laboratories, offering 212 comparisons including 60 involving a pharmacological treatment: 18 mg/kg/day fluoxetine. In addition, we define and use a dimensionless GxL factor, derived from dividing the GxL variance by the standard deviation between animals within groups, as the more robust vehicle to transfer the adjustment from the multi-lab analysis to very different labs and genotypes. For genotype comparisons, GxL-adjustment reduced the rate of non-replicable discoveries from 60% to 12%, for the price of reducing the power to make replicable discoveries from 87% to 66%. Another way to look at these results is noting that the adjustment could have prevented 23 failures to replicate, for the price of missing only three replicated ones. The tools and data needed for deployment of this method across other mouse experiments are publicly available in the Mouse Phenome Database. Our results further point at some phenotypes as more prone to produce non-replicable results, while others, known to be more difficult to measure, are as likely to produce replicable results (once adjusted) as the physiological body weight is.

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The ADNP Syndrome and CP201 (NAP) Potential and Hope

Cited by 34 publications

References 52 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

PACAP and NAP: Effect of Two Functionally Related Peptides in Diabetic Retinopathy

Improving replicability using interaction with laboratories: a multi-lab experimental assessment

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