Testing a New Gold Nanoparticle-Based Lithium Delivery Method for Bipolar Disorder in Laboratory Models

Official title

GSK-3 as a Target for Lithium-charged Au Nanoparticles in Bipolar Disorder

Overview

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.

Interventions

• Procedure Peripheral blood sampling for PBMC isolation
  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.

Primary outcome measures

• Intracellular lithium concentration in patient derived neural cells (hiNSCs) treated with LiG-AuNPs versus lithium salts (LiCl) [Time frame: 1, 2, 6, 12, and 24 hours after in vitro treatment (assessed throughout the 3-year study period)]

Secondary outcome measures (3)

• Functional and biophysical differences [Time frame: Assessed at 30 days of in vitro differentiation (within the 3-year study period)]
• Molecular biomarker expression in patient-derived neural cells [Time frame: Assessed at 30 days of in vitro differentiation (within the 3-year study period)]
• Blood biomarker profile in BD patients versus healthy controls [Time frame: Baseline (single blood draw) and up to 24 hours after in vitro lithium exposure (within the 3-year study period)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Roma

Publications

• 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. PMID 39404316
• 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. PMID 38884814
• 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. PMID 25541422
• 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. PMID 26804914
• 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. PMID 30870531
• 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. PMID 29321633
• 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. PMID 39236310
• 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. PMID 39564126

Identifiers

NCT: NCT07732933 · RF-2024-12379870

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗