Patient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies

Sabitha, K.R.; Shetty, Ashok K.; Upadhya, Dinesh

doi:10.1016/j.neubiorev.2020.12.025

Cited by 35 publications

(25 citation statements)

References 283 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The simultaneous culture of two or more cell types is possible allowing a physiological contextualization and recapitulation of the human biological systems [ 167 ]. hiPSC models have been used in ID-related disorders, such as Rett, Fragile-X, Dravet, Phelan-McDermid, Miller Dieker, Angelman, Prader-Willi, Timothy, Williams-Beuren and Lowe syndromes, Friedreich’s ataxia, Alexander and Pelizaeus-Merzbaucher diseases, primary microcephaly and X-linked adrenoleukodystrophy (reviewed by Sabitha et al [ 168 ]). The duration of the procedure and the expertise needed, are some of the limitations [ 169 ].…”

Section: Variant Deleteriousness Categorizationmentioning

confidence: 99%

“…Several CRISPR/Cas9-based studies have been carried out in hiPSCs, showing their efficiency and potential (reviewed by Ben Jehuda et al [ 176 ]). The use of CRISPR and hiPSCs simultaneously allows analysis in a donor-independent manner, overcoming the heterogeneity often observed in hiPSCs, due to the specific genetic background, epigenetic factors or other inter-individual differences [ 164 , 168 ]. One of the limitations of CRISPR/Cas-9 editing system is the off-target effects i.e.…”

Section: Variant Deleteriousness Categorizationmentioning

confidence: 99%

See 1 more Smart Citation

Intellectual disability genomics: current state, pitfalls and future challenges

et al. 2021

View full text Add to dashboard Cite

Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery.

show abstract

Section: Variant Deleteriousness Categorizationmentioning

confidence: 99%

Section: Variant Deleteriousness Categorizationmentioning

confidence: 99%

Intellectual disability genomics: current state, pitfalls and future challenges

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These rare neurodevelopmental diseases exhibit varied characteristics and different levels of severity due to genetic and epigenetic anomalies [ 75 ]. For example, Rett’s syndrome is mainly caused by mutations in methyl-CpG-binding protein 2 (MECP2) located in the X chromosome [ 76 ]. However, the severity and pathological characteristics are varied according to the type and location of the MECP2 mutations [ 77 ].…”

Section: Recapitulating Neuropsychiatric Disorders With Brain Organoidsmentioning

confidence: 99%

In Vitro Recapitulation of Neuropsychiatric Disorders with Pluripotent Stem Cells-Derived Brain Organoids

Gulimiheranmu

Zhou

2021

IJERPH

View full text Add to dashboard Cite

Adolescent neuropsychiatric disorders have been recently increasing due to genetic and environmental influences. Abnormal brain development before and after birth contribute to the pathology of neuropsychiatric disorders. However, it is difficult to experimentally investigate because of the complexity of brain and ethical constraints. Recently generated human brain organoids from pluripotent stem cells are considered as a promising in vitro model to recapitulate brain development and diseases. To better understand how brain organoids could be applied to investigate neuropsychiatric disorders, we analyzed the key consideration points, including how to generate brain organoids from pluripotent stem cells, the current application of brain organoids in recapitulating neuropsychiatric disorders and the future perspectives. This review covered what have been achieved on modeling the cellular and neural circuit deficits of neuropsychiatric disorders and those challenges yet to be solved. Together, this review aims to provide a fundamental understanding of how to generate brain organoids to model neuropsychiatric disorders, which will be helpful in improving the mental health of adolescents.

show abstract

“…Stem cell-derived neural cells are especially powerful models of embryonic development since differentiation protocols are typically designed to closely mimic key signaling pathways during early embryogenesis (for recent reviews see Imaizumi and Okano, 2021 ; Sabitha et al, 2021 ). Stem cell-derived neurons, whether in 2D or 3D culture, have been found to exhibit gene expression signatures that are most similar to early to mid-gestational stages (Handel et al, 2016 ; Logan et al, 2020 ).…”

Section: Complementing and Building On Animal Models With Human Stem Cell Modelsmentioning

confidence: 99%

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Knock

Julian

2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The brain is our most complex and least understood organ. Animal models have long been the most versatile tools available to dissect brain form and function; however, the human brain is highly distinct from that of standard model organisms. In addition to existing models, access to human brain cells and tissues is essential to reach new frontiers in our understanding of the human brain and how to intervene therapeutically in the face of disease or injury. In this review, we discuss current and developing culture models of human neural tissue, outlining advantages over animal models and key challenges that remain to be overcome. Our principal focus is on advances in engineering neural cells and tissue constructs from human pluripotent stem cells (PSCs), though primary human cell and slice culture are also discussed. By highlighting studies that combine animal models and human neural cell culture techniques, we endeavor to demonstrate that clever use of these orthogonal model systems produces more reproducible, physiological, and clinically relevant data than either approach alone. We provide examples across a range of topics in neuroscience research including brain development, injury, and cancer, neurodegenerative diseases, and psychiatric conditions. Finally, as testing of PSC-derived neurons for cell replacement therapy progresses, we touch on the advancements that are needed to make this a clinical mainstay.

show abstract

Patient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies

Cited by 35 publications

References 283 publications

Intellectual disability genomics: current state, pitfalls and future challenges

Intellectual disability genomics: current state, pitfalls and future challenges

In Vitro Recapitulation of Neuropsychiatric Disorders with Pluripotent Stem Cells-Derived Brain Organoids

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Contact Info

Product

Resources

About