Major depressive disorder (MDD; depression) is a mood disorder that causes a continued feeling of sadness and loss of interest. It is a common and serious illness that can cause both emotional and physical symptoms such as feelings of sadness, irritability, not being able to focus on activities, tiredness, changes in eating habits, and aches and pains. The main goal of the study is to evaluate how safe and effective fosigotifator is in treating MDD.
Fosigotifator (ABBV-CLS-7262) is a new treatment being developed for adult patients with depression. This study is double-blinded, which means that neither the patients nor the study doctors know who is given fosigotifator and who is given placebo. Participants will be randomly assigned to one of the two groups to receive fosigatofator or placebo. There is 1 in 2 chance that participants will receive placebo. Approximately 106 adult participants with MDD will be enrolled in approximately 15 sites across the world.
Participants will receive oral fosigotifator or matching placebo. Duration of the study is approximately 144 days.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular weekly visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Start Date23 Oct 2024

Sponsor / Collaborator

AbbVie, Inc.

NCT06425003 / CompletedPhase 1

Mass Balance Study of [14C] ABBV-CLS-7262 in Healthy Male Volunteers Following Single Oral Dose Administration

The purpose of this study is to evaluate mass balance, pharmacokinetics and safety of [14C] ABBV-CLS-7262 in healthy, male volunteers following administration of a single oral dose.

Start Date21 May 2024

Sponsor / Collaborator

Calico LLC

[+1]

NCT06310876 / CompletedPhase 1

A Phase 1 Placebo-and Active-Controlled Crossover Study of the Potential for Cardiac Repolarization Effects Following Single Dose of ABBV-CLS-7262 in Healthy Subjects

This is a randomized, blinded, placebo and active-controlled, 4-period, crossover design thorough QT/QTc (TQT) study to evaluate the effect of ABBV-CLS-7262 on cardiac repolarization in healthy adult subjects.

Start Date14 Mar 2024

Sponsor / Collaborator

Calico LLC

[+1]

100 Clinical Results associated with EIF2B1

100 Translational Medicine associated with EIF2B1

0 Patents (Medical) associated with EIF2B1

Literatures (Medical) associated with EIF2B1

13 Jul 2024·Cureus

Ovarioleukodystrophy Due to EIF2B Genes: Systematic Review and Case Report

Review

Author: Ramírez-García, Miguel Á ; Escobar-Pacheco, Mariana ; Yescas-Gómez, Petra ; Dávila-Ortiz de Montellano, David ; Luna-Álvarez, Mariana

Leukodystrophies comprise a spectrum of genetic disorders affecting white matter (WM) formation in the central nervous system (CNS), of which vanishing white matter disease (VWMD) is one. VWMD presents with progressive neurological deterioration and a variety of manifestations. Ovarioleukodystrophy, a subtype of VWMD, exhibits a distinctive clinical profile encompassing both CNS WM alterations and ovarian dysfunction. Variants in genes of the eukaryotic translation initiation factor 2B (EIF2B) complex affect the full form and are implicated in VWMD, including ovarioleukodystrophy. This work aimed to systematically review all published cases of ovarioleukodystrophy associated with variants in the EIF2B1-5 gene complex based on the first case identified in a Mexican population. We performed a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines of published cases of ovarioleukodystrophy associated with the EIF2B gene complex, including a newly identified case from Mexico. We identified 207 publications using PUBMED, SCOPUS, and PMC databases. One hundred fifty-one publications were eliminated due to duplicates, titles, abstracts, or other reasons, while 56 publications were revised, of which 29 were eliminated because they dealt with other genes or non-human research, and 27 reports were assessed for eligibility. Finally, 14 reports describing ovarian involvement, neuroimaging, and molecular variants were included. Our review identified 20 cases worldwide, with a median age of onset of 19 years. Clinical features included WM involvement, ovarian abnormalities, gait disturbances, epilepsy, cognitive and language impairment, and other neurological manifestations. Neuroimaging showed characteristic WM changes, highlighting the importance of MRI in diagnosis. Missense variants predominated among the identified genetic mutations, especially in the EIF2B4 and EIF2B5 genes. Ovarioleukodystrophy is an ultra-rare disorder with a wide range of clinical manifestations and ovarian changes. Gynecological evaluation is crucial in suspected cases of ovarioleukodystrophy, as ovarian manifestations may precede neurological symptoms. The role of MRI is crucial in the diagnostic approach to this entity. Continued collaborative efforts are essential to elucidate genotype-phenotype correlations, improve clinical management, and promote therapeutic advances for this rare disorder.

01 Sep 2023·Journal of neurology

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

Article

Author: do Carmo Macario, Maria ; Farina, Laura ; Castellani, Massimo ; Pareyson, Davide ; Gouveia, Ana ; Villacara, Alberto ; Piacentini, Sylvie ; Gellera, Cinzia ; Alvera, Sara ; Matos, Anabela ; Marotta, Giorgio ; Mantegazza, Renato ; Magri, Stefania ; Taroni, Franco ; Zito, Felicia Margherita ; Scaioli, Vidmer ; Cammarata, Gabriella ; Di Bella, Daniela ; Ciano, Claudia ; Bianchi-Marzoli, Stefania ; Salsano, Ettore ; Moscatelli, Marco ; Duraes, Joao ; Benzoni, Chiara

BACKGROUNDLeukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare.METHODSIn this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019.RESULTSWe identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. ¹H-spectroscopy primarily showed N-acetyl-aspartate reduction; ¹⁸fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2.CONCLUSIONSAO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

01 Apr 2023·CNS Neuroscience & Therapeutics

Human‐induced pluripotent stem cell‐derived cerebral organoid of leukoencephalopathy with vanishing white matter

Article

Author: Wu, Ye ; Deng, Jiong ; Zhou, Ling ; Jiang, Yuwu ; Zhang, Jie ; Gao, Kai ; Wang, Jingmin

AbstractIntroductionLeukoencephalopathy with vanishing white matter (VWM) is a rare autosomal recessive leukoencephalopathy resulting from mutations in EIF2B1‐5, which encode subunits of eukaryotic translation initiation factor 2B (eIF2B). Studies have found that eIF2B mutation has a certain influence on embryonic brain development. So far, the effect of the eIF2B mutations on the dynamic process of brain development is not fully understood yet.AimsThree‐dimensional brain organoid technology has promoted the study of human nervous system developmental diseases in recent years, providing a potential platform for elucidating the pathological mechanism of neurodevelopmental diseases. In this study, we aimed to investigate the effects of eIF2B mutation on the differentiation and development of different nerve cells during dynamic brain development process using 3D brain organoids.ResultsWe constructed eIF2B mutant and wild‐type brain organoid model with induced pluripotent stem cell (iPSC). Compared with the wild type, the mutant brain organoids were significantly smaller, accompanied by increase in apoptosis, which might be resulted from overactivation of unfolded protein response (UPR). Neuronal development was delayed in early stage, but with normal superficial neuronal differentiation in later stage. eIF2B mutations resulted in immature astrocytes with increased expression of GFAPδ, nestin, and αB‐crystallin, and there were increased oligodendrocyte progenitor cells, decreased mature oligodendrocytes, and sparse myelin in mutant cerebral organoids in the later stage.Conclusionwe constructed the first eIF2B mutant cerebral organoids to explore the dynamic brain development process, which provides a platform for further research on the specific pathogenesis of VWM.

News (Medical) associated with EIF2B1

03 Sep 2021

·www.pharmatimes.com

BMS opts-in on Evotec's neurodegenerative medicine

Bristol Myers Squibb (BMS) has opted-in to an exclusive global license for Evotec’s neurodegenerative drug EVT8683. The deal is the first programme to emerge from the two companies’ collaboration in neurodegeneration, which was initiated in 2016. Evotec originally signed the collaboration deal with Celgene, which was subsequently acquired by BMS in 2019. EVT8683 is a small molecule targeting a key cellular stress response which has the potential to deliver disease-modifying treatments for several neurodegenerative diseases. The EVT8683 programme originates from a phenotypic screen conducted by Evotec using its IPSC (induced pluripotent stem cell) drug discovery platform. Under the terms of the deal, Evotec has received an option payment of $20 m and is eligible to earn up to $250m in milestone payments. Cord Dohrmann, chief scientific officer of Evotec, commented: “We are very excited to bring a first drug candidate which originated from Evotec’s iPSC discovery platform into the clinic. EVT8683 is targeting a highly promising mechanism of the cellular stress response and has already demonstrated a very compelling pre-clinical efficacy and safety profile. Richard Hargreaves, senior vice president of BMS’s Neuroscience Thematic Research Centre, added: “Targeting one of the mechanisms which may play a key role within neurodegeneration makes us hopeful that our further development of the program may result in providing treatments for many people suffering from these devastating neurological disorders. Based on Evotec’s scientific expertise and seamless integration, we are delighted to continue development of this clinical candidate.”

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