Modeling genetic epileptic encephalopathies using brain organoids

Steinberg, Daniel J.; Repudi, Srinivasarao; Saleem, Afifa; Kustanovich, I. M.; Viukov, Sergey; Abudiab, Baraa; Banne, Ehud; Mahajnah, Muhammad; Hanna, Jacob; Stern, Shani; Carlen, Peter L.; Aqeilan, Rami I.

doi:10.15252/emmm.202013610

Cited by 37 publications

(32 citation statements)

References 93 publications

(134 reference statements)

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“…Although unknown, this fits the description of limited expression of WWOX mRNA during human embryonic development. This connection was further supported when upon prolonged culturing WWOX expression appeared in non-RG cells [57], and in another organoids model of ours, was even found in neurons [44]. This pattern is highlighted in Figure 1.…”

Section: Wwox In Brain Organoidssupporting

confidence: 76%

“…The second hallmark, gliosis, which was also previously described in Wwox-null mice [49] but not in rats [30], was addressed by quantifying the expression of the astrocytic markers GFAP and S100β, both at protein and RNA levels, with additional markers (AQP4 and ALDH1A1) also quantified at the RNA level. Overall, WWOX-KO organoids demonstrated increased astrogenesis, which progressed with time [57].…”

Section: Wwox In Brain Organoidsmentioning

confidence: 96%

“…Another observation was increased neuronal apoptosis in Wwox-null mice [50]. Together with the reduced proliferation in the SVZ discussed above, these findings are very important because high WWOX expression is usually associated with enhanced apoptosis [16,55,56], and loss of WWOX is associated with reduced check-point inhibition [12,13,15,57].…”

Section: Micementioning

confidence: 99%

“…To do that, we generated WWOX-KO hESCs from the WiBR3 cell line. These cells were then used to generate WWOX-KO cerebral organoids (COs) [57]. After validating the organoids, the first step was to find out if the organoids can recapitulate hallmarks of epilepsy, such as neuronal hyperexcitability and gliosis [33][34][35]37].…”

Section: Wwox In Brain Organoidsmentioning

confidence: 99%

“…Moreover, organoids have been successfully used to model many brain pathologies [105,106]. These include but are not limited to viral infections (Zika, herpes simplex virus 1 and SARS-CoV-2) [114,[152][153][154][155], brain tumors [156][157][158][159], microcephaly [108,153,160,161], neuropsychiatric disorders [162][163][164], ASD [165,166], neurodegenerative disorders (Alzheimer's disease, Parkinson's disease and fronto-temporal dementia) [138,[167][168][169][170][171], lissencephaly (Miller-Dieker syndrome; also associated with epilepsy) [172], and seizure related disorders [173] such as tuberous sclerosis [174], Angelman syndrome [175], Rett syndrome [176], Timothy syndrome [127], and developmental epileptic encephalopathies (UGDH gene mutations) [177], SCAR12 and WOREE syndromes [44,57].…”

Section: Human Systems Introduction To Brain Organoidsmentioning

confidence: 99%

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WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

Steinberg

Aqeilan

2021

Cells

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The WW domain-containing oxidoreductase (WWOX) gene was originally discovered as a putative tumor suppressor spanning the common fragile site FRA16D, but as time has progressed the extent of its pleiotropic function has become apparent. At present, WWOX is a major source of interest in the context of neurological disorders, and more specifically developmental and epileptic encephalopathies (DEEs). This review article aims to introduce the many model systems used through the years to study its function and roles in neuropathies. Similarities and fundamental differences between rodent and human models are discussed. Finally, future perspectives and promising research avenues are suggested.

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Section: Wwox In Brain Organoidssupporting

confidence: 76%

Section: Wwox In Brain Organoidsmentioning

confidence: 96%

Section: Micementioning

confidence: 99%

Section: Wwox In Brain Organoidsmentioning

confidence: 99%

Section: Human Systems Introduction To Brain Organoidsmentioning

confidence: 99%

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WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

Steinberg

Aqeilan

2021

Cells

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Pluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries

Lancaster

2024

BioEssays

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Organoids are quickly becoming an accepted model for understanding human biology and disease. Pluripotent stem cells (PSC) provide a starting point for many organs and enable modeling of the embryonic development and maturation of such organs. The foundation of PSC‐derived organoids can be found in elegant developmental studies demonstrating the remarkable ability of immature cells to undergo histogenesis even when taken out of the embryo context. PSC‐organoids are an evolution of earlier methods such as embryoid bodies, taken to a new level with finer control and in some cases going beyond tissue histogenesis to organ‐like morphogenesis. But many of the discoveries that led to organoids were not necessarily planned, but rather the result of inquisitive minds with freedom to explore. Protecting such curiosity‐led research through flexible funding will be important going forward if we are to see further ground‐breaking discoveries.

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In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

Danačíková,

Straka,

Daněk

et al. 2024

Epilepsia Open

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Epilepsy is the most common chronic neurological disease, affecting nearly 1%–2% of the world's population. Current pharmacological treatment and regimen adjustments are aimed at controlling seizures; however, they are ineffective in one‐third of the patients. Although neuronal hyperexcitability was previously thought to be mainly due to ion channel alterations, current research has revealed other contributing molecular pathways, including processes involved in cellular signaling, energy metabolism, protein synthesis, axon guidance, inflammation, and others. Some forms of drug‐resistant epilepsy are caused by genetic defects that constitute potential targets for precision therapy. Although such approaches are increasingly important, they are still in the early stages of development. This review aims to provide a summary of practical aspects of the employment of in vitro human cell culture models in epilepsy diagnosis, treatment, and research. First, we briefly summarize the genetic testing that may result in the detection of candidate pathogenic variants in genes involved in epilepsy pathogenesis. Consequently, we review existing in vitro cell models, including induced pluripotent stem cells and differentiated neuronal cells, providing their specific properties, validity, and employment in research pipelines. We cover two methodological approaches. The first approach involves the utilization of somatic cells directly obtained from individual patients, while the second approach entails the utilization of characterized cell lines. The models are evaluated in terms of their research and clinical benefits, relevance to the in vivo conditions, legal and ethical aspects, time and cost demands, and available published data. Despite the methodological, temporal, and financial demands of the reviewed models they possess high potential to be used as robust systems in routine testing of pathogenicity of detected variants in the near future and provide a solid experimental background for personalized therapy of genetic epilepsies.Plain Language SummaryEpilepsy affects millions worldwide, but current treatments fail for many patients. Beyond traditional ion channel alterations, various genetic factors contribute to the disorder's complexity. This review explores how in vitro human cell models, either from patients or from cell lines, can aid in understanding epilepsy's genetic roots and developing personalized therapies. While these models require further investigation, they offer hope for improved diagnosis and treatment of genetic forms of epilepsy.

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Modeling genetic epileptic encephalopathies using brain organoids

Cited by 37 publications

References 93 publications

WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

Pluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries

In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

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