- ICH GCP
- Registre américain des essais cliniques
- Essai clinique NCT07732933
Testing a New Gold Nanoparticle-Based Lithium Delivery Method for Bipolar Disorder in Laboratory Models (GLAD)
GSK-3 as a Target for Lithium-charged Au Nanoparticles in Bipolar Disorder
This preclinical translational study aims to evaluate a new method of delivering lithium using gold nanoparticles for the treatment of bipolar disorder. Lithium is an effective treatment for bipolar disorder, but its clinical use is limited by a narrow therapeutic range and the risk of side effects. The study will investigate whether gold nanoparticles carrying lithium can improve lithium delivery to brain cells while reducing exposure to other tissues.
The research will use human induced pluripotent stem cell (iPSC)-derived neural cells generated from blood samples collected from people with bipolar disorder and healthy volunteers, as well as a mouse model of mania. No participants will receive the investigational treatment. Human participants will provide blood samples only for the generation of laboratory cell models.
The study will compare the effects of nanoparticle-delivered lithium with conventional lithium salts on cellular lithium uptake, disease-related molecular and functional changes, and biomarkers associated with bipolar disorder. The hypothesis is that lithium delivered by gold nanoparticles will achieve greater therapeutic effects at lower systemic lithium exposure than conventional lithium formulations, providing proof of concept for a safer and more targeted lithium delivery strategy for future clinical development.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Type d'étude
Inscription (Estimé)
Phase
- N'est pas applicable
Contacts et emplacements
Coordonnées de l'étude
- Nom: Gabriele Sani
- Numéro de téléphone: +39 06 30155807
- E-mail: gabriele.sani@policlinicogemelli.it
Lieux d'étude
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Roma, Italie, 00168
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS
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Contact:
- Gabriele Sani
- Numéro de téléphone: +39 06 30155807
- E-mail: gabriele.sani@policlinicogemelli.it
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
La description
Inclusion Criteria:
Inclusion criteria for patients
- Age: 18-65 years.
- Diagnosis of Bipolar I or Bipolar II Disorder, according to DSM-5 criteria.
- Currently in a depressive, manic, hypomanic, mixed, or euthymic phase, as defined by DSM-5 and clinical evaluation.
- No use of psychotropic medications during the 12 months preceding enrollment, except for low-dose benzodiazepines or antipsychotics used intermittently to manage sleep disturbances or anxiety symptoms.
- No prior treatment with lithium at any point in the patient's psychiatric history.
- Medically stable and deemed suitable for study participation.
- Ability and willingness to provide written informed consent before any study procedure For the Human Healthy Control group
- participants aged 18-65 years will be included, while subjects with DSM-5 disorders or a family history of psychiatric disorders will be excluded.
Exclusion Criteria:
- Current or past diagnosis of schizophrenia, schizoaffective disorder, or borderline personality disorder as the primary psychiatric condition.
- Diagnosis of moderate to severe substance use disorder (excluding nicotine) within the past 12 months.
- Active suicidal ideation with plan or intent
- History of major neurological disorders, including epilepsy, traumatic brain injury, or neurodegenerative disease.
- Previous exposure to lithium at any point in the individual's psychiatric history.
- Use of psychotropic medication within the 12 months before enrollment.
- Presence of uncontrolled or clinically significant medical conditions, including but not limited to severe hepatic, renal, or cardiovascular disease.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: N / A
- Modèle interventionnel: Affectation à un seul groupe
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Expérimental: Biological sample collection for iPSC/hiNSC generation
Includes both patients with Bipolar I or II Disorder (per DSM-5 criteria) and Human Healthy Controls (HC), recruited at the UOC of Clinical and Emergency Psychiatry, Fondazione Policlinico Universitario A. Gemelli IRCCS.
All participants undergo the same peripheral blood sampling procedure, with no drug or device administered.
The distinction between BD patients and healthy controls is defined by eligibility/diagnostic criteria, not by assignment or randomization to distinct arms
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Blood collection in EDTA tubes for isolation of peripheral blood mononuclear cells (PBMCs), followed by reprogramming into induced pluripotent stem cells (iPSCs) via Sendai virus infection and differentiation into human induced neural stem cells (hiNSCs), used for the in vitro experiments of the protocol.
No drug or device is administered to participants.
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Intracellular lithium concentration in patient derived neural cells (hiNSCs) treated with LiG-AuNPs versus lithium salts (LiCl)
Délai: 1, 2, 6, 12, and 24 hours after in vitro treatment (assessed throughout the 3-year study period)
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Quantification of intracellular lithium load by Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) and subcellular gold nanoparticle distribution by Transmission Electron Microscopy (TEM) in neurons, astrocytes, and oligodendrocytes differentiated from participant-derived human induced Neural Stem Cells (hiNSCs), treated with Lithium-loaded, Glutathione-coated Gold Nanoparticles (LiG-AuNPs) or Lithium Chloride (LiCl) at concentrations of 0.15, 0.5, 1, 3, and 6 mEq/L, to compare uptake efficiency between the two delivery methods.
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1, 2, 6, 12, and 24 hours after in vitro treatment (assessed throughout the 3-year study period)
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
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Functional and biophysical differences
Délai: Assessed at 30 days of in vitro differentiation (within the 3-year study period)
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Comparison of neuronal parameters (resting membrane potential, action potential threshold, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) current ratio, frequency/amplitude of miniature excitatory postsynaptic currents, synaptic vesicle release) and astrocytic parameters (intracellular Ca²⁺ signaling, glutamate buffering/Excitatory Amino Acid Transporter 2 (EAAT2) activity, gliotransmitter release) between human induced Neural Stem Cell (hiNSC)-derived neurons/astrocytes from Bipolar Disorder (BD) patients versus healthy controls, before and after lithium exposure.
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Assessed at 30 days of in vitro differentiation (within the 3-year study period)
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Molecular biomarker expression in patient-derived neural cells
Délai: Assessed at 30 days of in vitro differentiation (within the 3-year study period)
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Levels of c-Fos, Synaptotagmin-7, Neuronal Pentraxin 2 (NPTX2), B-cell lymphoma 2 (Bcl-2), phospho-Glycogen Synthase Kinase 3 beta (GSK-3β)(Ser9)/total GSK-3β, and phospho-cytosolic Phospholipase A2 (cPLA2)(Ser505)/total cPLA2 in human induced Neural Stem Cell (hiNSC)-derived neurons and astrocytes from Bipolar Disorder (BD) patients.
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Assessed at 30 days of in vitro differentiation (within the 3-year study period)
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Blood biomarker profile in BD patients versus healthy controls
Délai: Baseline (single blood draw) and up to 24 hours after in vitro lithium exposure (within the 3-year study period)
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Plasma lithium levels, Thyroid Stimulating Hormone (TSH) levels, lithium load in blood cells, phospho-Glycogen Synthase Kinase 3 beta (pGSK-3β)(Ser9)/total GSK-3β ratio, and phospho-cytosolic Phospholipase A2 (cPLA2)(Ser505)/total cPLA2 levels, measured in blood cells and plasma from Bipolar Disorder (BD) patients (during the manic phase and again after standard lithium therapy) and from healthy controls, for comparison and biomarker identification.
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Baseline (single blood draw) and up to 24 hours after in vitro lithium exposure (within the 3-year study period)
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Collaborateurs et enquêteurs
Les enquêteurs
- Chercheur principal: Gabriele Sani, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Publications et liens utiles
Publications générales
- Rosati J, Ferrari D, Altieri F, Tardivo S, Ricciolini C, Fusilli C, Zalfa C, Profico DC, Pinos F, Bernardini L, Torres B, Manni I, Piaggio G, Binda E, Copetti M, Lamorte G, Mazza T, Carella M, Gelati M, Valente EM, Simeone A, Vescovi AL. Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies. Cell Death Dis. 2018 Sep 17;9(10):937. doi: 10.1038/s41419-018-0990-2.
- Buonerba A, Lapenta R, Della Monica F, Piacentini R, Baldino L, Scognamiglio MR, Speranza V, Milione S, Capacchione C, Rieger B, Grassi A. Thermo- and Photoresponsive Smart Nanomaterial Based on Poly(diethyl vinyl phosphonate)-Capped Gold Nanoparticles. Nanomaterials (Basel). 2024 Oct 1;14(19):1589. doi: 10.3390/nano14191589.
- Aceto G, Nardella L, Nanni S, Pecci V, Bertozzi A, Nutarelli S, Viscomi MT, Colussi C, D'Ascenzo M, Grassi C. Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens. Cell Mol Life Sci. 2024 Jun 17;81(1):268. doi: 10.1007/s00018-024-05260-w.
- Scala F, Fusco S, Ripoli C, Piacentini R, Li Puma DD, Spinelli M, Laezza F, Grassi C, D'Ascenzo M. Intraneuronal Abeta accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3. Neurobiol Aging. 2015 Feb;36(2):886-900. doi: 10.1016/j.neurobiolaging.2014.10.034. Epub 2014 Nov 4.
- Fusco S, Leone L, Barbati SA, Samengo D, Piacentini R, Maulucci G, Toietta G, Spinelli M, McBurney M, Pani G, Grassi C. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability. Cell Rep. 2016 Feb 9;14(5):1195-1205. doi: 10.1016/j.celrep.2015.12.092. Epub 2016 Jan 21.
- De Chiara G, Piacentini R, Fabiani M, Mastrodonato A, Marcocci ME, Limongi D, Napoletani G, Protto V, Coluccio P, Celestino I, Li Puma DD, Grassi C, Palamara AT. Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog. 2019 Mar 14;15(3):e1007617. doi: 10.1371/journal.ppat.1007617. eCollection 2019 Mar.
- Mastrodonato A, Barbati SA, Leone L, Colussi C, Gironi K, Rinaudo M, Piacentini R, Denny CA, Grassi C. Olfactory memory is enhanced in mice exposed to extremely low-frequency electromagnetic fields via Wnt/beta-catenin dependent modulation of subventricular zone neurogenesis. Sci Rep. 2018 Jan 10;8(1):262. doi: 10.1038/s41598-017-18676-1.
- Tropea MR, Melone M, Li Puma DD, Vacanti V, Aceto G, Bandiera B, Trovato RC, Torrisi SA, Leggio GM, Palmeri A, D'Ascenzo M, Conti F, Grassi C, Puzzo D. Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age-related cognitive phenotype. Aging Cell. 2024 Nov;23(11):e14291. doi: 10.1111/acel.14291. Epub 2024 Sep 5.
- Bandiera B, Natale F, Rinaudo M, Sollazzo R, Spinelli M, Fusco S, Grassi C. Olfactory stimulation with multiple odorants prevents stress-induced cognitive and psychological alterations. Brain Commun. 2024 Nov 5;6(6):fcae390. doi: 10.1093/braincomms/fcae390. eCollection 2024.
- Markov DD. Sucrose Preference Test as a Measure of Anhedonic Behavior in a Chronic Unpredictable Mild Stress Model of Depression: Outstanding Issues. Brain Sci. 2022 Sep 24;12(10):1287. doi: 10.3390/brainsci12101287.
- Puliatti G, Li Puma DD, Aceto G, Lazzarino G, Acquarone E, Mangione R, D'Adamio L, Ripoli C, Arancio O, Piacentini R, Grassi C. Intracellular accumulation of tau oligomers in astrocytes and their synaptotoxic action rely on Amyloid Precursor Protein Intracellular Domain-dependent expression of Glypican-4. Prog Neurobiol. 2023 Aug;227:102482. doi: 10.1016/j.pneurobio.2023.102482. Epub 2023 Jun 14.
- Li Puma DD, Ripoli C, Puliatti G, Pastore F, Lazzarino G, Tavazzi B, Arancio O, Piacentini R, Grassi C. Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function. Neuropathol Appl Neurobiol. 2022 Aug;48(5):e12811. doi: 10.1111/nan.12811. Epub 2022 Mar 16.
- Ripoli C, Cocco S, Li Puma DD, Piacentini R, Mastrodonato A, Scala F, Puzzo D, D'Ascenzo M, Grassi C. Intracellular accumulation of amyloid-beta (Abeta) protein plays a major role in Abeta-induced alterations of glutamatergic synaptic transmission and plasticity. J Neurosci. 2014 Sep 17;34(38):12893-903. doi: 10.1523/JNEUROSCI.1201-14.2014.
- Li X, Chen B, Zhang D, Wang S, Feng Y, Wu X, Cui L, Ji M, Gong W, Verkhratsky A, Xia M, Li B. A novel murine model of mania. Mol Psychiatry. 2023 Jul;28(7):3044-3054. doi: 10.1038/s41380-023-02037-8. Epub 2023 Mar 29.
- Buonerba A, Lapenta R, Donniacuo A, Licasale M, Vezzoli E, Milione S, Capacchione C, Tecce MF, Falqui A, Piacentini R, Grassi C, Grassi A. NIR multiphoton ablation of cancer cells, fluorescence quenching and cellular uptake of dansyl-glutathione-coated gold nanoparticles. Sci Rep. 2020 Jul 9;10(1):11380. doi: 10.1038/s41598-020-68397-1.
Liens utiles
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Estimé)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- RF-2024-12379870
Plan pour les données individuelles des participants (IPD)
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Description du régime IPD
Informations sur les médicaments et les dispositifs, documents d'étude
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