Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines

Kaewkhaw, Rossukon; Swaroop, Manju; Homma, Kyoji; Nakamura, Jutaro; Brooks, Matthew; Kaya, Koray Dogan; Chaitankar, Vijender; Michael, Sam; Tawa, Gregory J.; Zou, Jizhong; Rao, Mahendra S.; Zheng, Wei; Cogliati, Tiziana; Swaroop, Anand

doi:10.1167/iovs.15-17639

Cited by 33 publications

(24 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…WES and targeted sequencing are becoming standard methodology for identifying genetic variants/mutations in retinal research and clinical diagnosis. NGS-based methods are increasingly being used to evaluate drug targets and small molecules and their broader impact on retinal cell/tissue function (Chen and Palczewski, 2015; Kaewkhaw, 2016). Over 240 genes have so far been associated with retinal diseases; however, underlying pathways leading to disease pathology are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, the use of human pluripotent stem cells (hPSCs), especially induced pluripotent stem cells (iPSCs), has significantly expanded the focus on investigating human disease (Merkle and Eggan, 2013). hPSCs are becoming routine for developmental studies and screening small molecules to rescue disease-associated phenotypes (Kaewkhaw et al, 2015; Kaewkhaw et al, 2016), offering immense opportunities in combination with NGS to make precision medicine a reality in the near future.…”

Section: Genomementioning

confidence: 99%

See 1 more Smart Citation

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research

Chaitankar

Karakülah

Ratnapriya

et al. 2016

Progress in Retinal and Eye Research

Self Cite

View full text Add to dashboard Cite

The advent of high throughput next generation sequencing (NGS) has accelerated the pace of discovery of disease-associated genetic variants and genomewide profiling of expressed sequences and epigenetic marks, thereby permitting systems-based analyses of ocular development and disease. Rapid evolution of NGS and associated methodologies presents significant challenges in acquisition, management, and analysis of large data sets and for extracting biologically or clinically relevant information. Here we illustrate the basic design of commonly used NGS-based methods, specifically whole exome sequencing, transcriptome, and epigenome profiling, and provide recommendations for data analyses. We briefly discuss systems biology approaches for integrating multiple data sets to elucidate gene regulatory or disease networks. While we provide examples from the retina, the NGS guidelines reviewed here are applicable to other tissues/cell types as well.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Genomementioning

confidence: 99%

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research

Chaitankar

Karakülah

Ratnapriya

et al. 2016

Progress in Retinal and Eye Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Proof-of-concept studies have been performed to target disease-relevant molecular pathways using human iPSC-derived somatic cells with promising results [165]. Stem cell-based 2-D photoreceptors and 3-D retinal organoids provide a valuable clinically relevant resource for HTS to develop effective drugs for retinal ciliopathies [166,167].…”

Section: Drug Discoverymentioning

confidence: 99%

Retinal disease in ciliopathies: Recent advances with a focus on stem cell-based therapies

Chen

Welby

et al. 2019

TRD

Self Cite

View full text Add to dashboard Cite

Ciliopathies display extensive genetic and clinical heterogeneity, varying in severity, age of onset, disease progression and organ systems affected. Retinal involvement, as demonstrated by photoreceptor dysfunction or death, is a highly penetrant phenotype among a vast majority of ciliopathies. Photoreceptor cells possess a specialized and modified sensory cilium with membrane discs where efficient photon capture and ensuing signaling cascade initiate the visual process. Disruptions of cilia biogenesis and protein transport lead to impairment of photoreceptor function and eventually degeneration. Despite advances in elucidation of ciliogenesis and photoreceptor cilia defects, we have limited understanding of pathogenic mechanisms underlying retinal phenotype(s) observed in human ciliopathies. Patient-derived induced pluripotent stem cell (iPSC)-based approaches offer a unique opportunity to complement studies with model organisms and examine cilia disease relevant to humans. Three-dimensional retinal organoids from iPSC lines feature laminated cytoarchitecture, apical-basal polarity and emergence of a ciliary structure, thereby permitting pathogenic modeling of human photoreceptors in vitro. Here, we review the biology of photoreceptor cilia and associated defects and discuss recent progress in evolving treatment modalities, especially using patient-derived iPSCs, for retinal ciliopathies.

show abstract

“…Second, patient phenotyping can be improved through the use of disease models and transcriptomics, providing greater insight into the underlying pathway dynamics. Third, optimal human retinal-disease-in-a-dish procedures allow improved treatment paradigms for the patient (Kaewkhaw et al, 2016; Völkner et al, 2016). Lastly, this approach allows researchers to develop strategies designed to correct point mutations and exon insertions in both dividing and non-dividing neurons using CRISPR/Cas9-based editing (Bassuk et al, 2016; Suzuki et al, 2016).…”

Section: Personalized Medicine: Still Not Yet the Ideal Situationmentioning

confidence: 99%

The CRB1 Complex: Following the Trail of Crumbs to a Feasible Gene Therapy Strategy

2017

View full text Add to dashboard Cite

Once considered science fiction, gene therapy is rapidly becoming scientific reality, targeting a growing number of the approximately 250 genes linked to hereditary retinal disorders such as retinitis pigmentosa and Leber's congenital amaurosis. Powerful new technologies have emerged, leading to the development of humanized models for testing and screening these therapies, bringing us closer to the goal of personalized medicine. These tools include the ability to differentiate human induced pluripotent stem cells (iPSCs) to create a “retina-in-a-dish” model and the self-formed ectodermal autonomous multi-zone, which can mimic whole eye development. In addition, highly specific gene-editing tools are now available, including the CRISPR/Cas9 system and the recently developed homology-independent targeted integration approach, which allows gene editing in non-dividing cells. Variants in the CRB1 gene have long been associated with retinopathies, and more recently the CRB2 gene has also been shown to have possible clinical relevance with respect to retinopathies. In this review, we discuss the role of the CRB protein complex in patients with retinopathy. In addition, we discuss new opportunities provided by stem cells and gene-editing tools, and we provide insight into how the retinal therapeutic pipeline can be improved. Finally, we discuss the current state of adeno-associated virus-mediated gene therapy and how it can be applied to treat retinopathies associated with mutations in CRB1.

show abstract

Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines

Cited by 33 publications

References 66 publications

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research

Retinal disease in ciliopathies: Recent advances with a focus on stem cell-based therapies

The CRB1 Complex: Following the Trail of Crumbs to a Feasible Gene Therapy Strategy

Contact Info

Product

Resources

About