scholarly journals Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development

2020 ◽  
Vol 9 (3) ◽  
pp. 644 ◽  
Author(s):  
Noelia Benetó ◽  
Monica Cozar ◽  
Laura Castilla-Vallmanya ◽  
Oskar G. Zetterdahl ◽  
Madalina Sacultanu ◽  
...  
Keyword(s):  
Drug Development ◽  
Disease Modeling ◽  
Neuronal Model ◽  
Therapeutic Interventions ◽  
Neural Cells ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Cellular Models ◽  
Disease Mechanisms

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.

scholarly journals Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

2020 ◽  
Vol 21 (21) ◽  
pp. 7819
Author(s):  
Noelia Benetó ◽  
Lluïsa Vilageliu ◽  
Daniel Grinberg ◽  
Isaac Canals
Keyword(s):  
Heparan Sulfate ◽  
Disease Modeling ◽  
Neuronal Degeneration ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Therapeutic Approaches ◽  
Cellular Mechanisms ◽  
Cellular Models ◽  
Induced Pluripotent ◽  
Cellular Dysfunction

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.

scholarly journals From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Alexandra Gatzios ◽  
Matthias Rombaut ◽  
Karolien Buyl ◽  
Joery De Kock ◽  
Robim M. Rodrigues ◽  
...  
Keyword(s):  
Liver Disease ◽  
Drug Development ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Testing ◽  
Disease Modeling ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

scholarly journals Human Organoids for Predictive Toxicology Research and Drug Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Toshikatsu Matsui ◽  
Tadahiro Shinozawa
Keyword(s):  
Stem Cells ◽  
Drug Development ◽  
Disease Modeling ◽  
Cell Types ◽  
Underlying Disease ◽  
Future Research ◽  
Specific Cell ◽  
Predictive Toxicology

Organoids are three-dimensional structures fabricated in vitro from pluripotent stem cells or adult tissue stem cells via a process of self-organization that results in the formation of organ-specific cell types. Human organoids are expected to mimic complex microenvironments and many of the in vivo physiological functions of relevant tissues, thus filling the translational gap between animals and humans and increasing our understanding of the mechanisms underlying disease and developmental processes. In the last decade, organoid research has attracted increasing attention in areas such as disease modeling, drug development, regenerative medicine, toxicology research, and personalized medicine. In particular, in the field of toxicology, where there are various traditional models, human organoids are expected to blaze a new path in future research by overcoming the current limitations, such as those related to differences in drug responses among species. Here, we discuss the potential usefulness, limitations, and future prospects of human liver, heart, kidney, gut, and brain organoids from the viewpoints of predictive toxicology research and drug development, providing cutting edge information on their fabrication methods and functional characteristics.

scholarly journals Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1001 ◽  
Author(s):  
Agapios Sachinidis
Keyword(s):  
Heart Failure ◽  
Stem Cell ◽  
Anticancer Drugs ◽  
Disease Modeling ◽  
Drug Induced ◽  
Short Treatment ◽  
Cellular Models ◽  
Therapeutic Concepts ◽  
Induced Pluripotent

Human-induced pluripotent stem cells (hiPSCs) are discussed as disease modeling for optimization and adaptation of therapy to each individual. However, the fundamental question is still under debate whether stem-cell-based disease modeling and drug discovery are applicable for recapitulating pathological processes under in vivo conditions. Drug treatment and exposure to different chemicals and environmental factors can initiate diseases due to toxicity effects in humans. It is well documented that drug-induced cardiotoxicity accelerates the development of heart failure (HF). Until now, investigations on the understanding of mechanisms involved in HF by anticancer drugs are hindered by limitations of the available cellular models which are relevant for human physiology and by the fact that the clinical manifestation of HF often occurs several years after its initiation. Recently, we identified similar genomic biomarkers as observed by HF after short treatment of hiPSCs-derived cardiomyocytes (hiPSC-CMs) with different antitumor drugs such as anthracyclines and etoposide (ETP). Moreover, we identified common cardiotoxic biological processes and signal transduction pathways which are discussed as being crucial for the survival and function of cardiomyocytes and, therefore, for the development of HF. In the present review, I discuss the applicability of the in vitro cardiotoxicity test systems as modeling for discovering preventive mechanisms/targets against cardiotoxicity and, therefore, for novel HF therapeutic concepts.

scholarly journals Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3483
Author(s):  
Mohamed M. Bekhite ◽  
P. Christian Schulze
Keyword(s):  
Stem Cell ◽  
Heart Disease ◽  
Drug Development ◽  
Pluripotent Stem Cell ◽  
Human Heart ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Development Platform ◽  
Induced Pluripotent

A comprehensive understanding of the pathophysiology and cellular responses to drugs in human heart disease is limited by species differences between humans and experimental animals. In addition, isolation of human cardiomyocytes (CMs) is complicated because cells obtained by biopsy do not proliferate to provide sufficient numbers of cells for preclinical studies in vitro. Interestingly, the discovery of human-induced pluripotent stem cell (hiPSC) has opened up the possibility of generating and studying heart disease in a culture dish. The combination of reprogramming and genome editing technologies to generate a broad spectrum of human heart diseases in vitro offers a great opportunity to elucidate gene function and mechanisms. However, to exploit the potential applications of hiPSC-derived-CMs for drug testing and studying adult-onset cardiac disease, a full functional characterization of maturation and metabolic traits is required. In this review, we focus on methods to reprogram somatic cells into hiPSC and the solutions for overcome immaturity of the hiPSC-derived-CMs to mimic the structure and physiological properties of the adult human CMs to accurately model disease and test drug safety. Finally, we discuss how to improve the culture, differentiation, and purification of CMs to obtain sufficient numbers of desired types of hiPSC-derived-CMs for disease modeling and drug development platform.

scholarly journals A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 967
Author(s):  
Yasmin Roye ◽  
Rohan Bhattacharya ◽  
Xingrui Mou ◽  
Yuhao Zhou ◽  
Morgan A. Burt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Kidney Disease ◽  
Structural Integrity ◽  
Disease Modeling ◽  
Patient Specific ◽  
Ips Cell ◽  
Filtration Barrier ◽  
Disease Mechanisms ◽  
Kidney Glomerulus

Progress in understanding kidney disease mechanisms and the development of targeted therapeutics have been limited by the lack of functional in vitro models that can closely recapitulate human physiological responses. Organ Chip (or organ-on-a-chip) microfluidic devices provide unique opportunities to overcome some of these challenges given their ability to model the structure and function of tissues and organs in vitro. Previously established organ chip models typically consist of heterogenous cell populations sourced from multiple donors, limiting their applications in patient-specific disease modeling and personalized medicine. In this study, we engineered a personalized glomerulus chip system reconstituted from human induced pluripotent stem (iPS) cell-derived vascular endothelial cells (ECs) and podocytes from a single patient. Our stem cell-derived kidney glomerulus chip successfully mimics the structure and some essential functions of the glomerular filtration barrier. We further modeled glomerular injury in our tissue chips by administering a clinically relevant dose of the chemotherapy drug Adriamycin. The drug disrupts the structural integrity of the endothelium and the podocyte tissue layers, leading to significant albuminuria as observed in patients with glomerulopathies. We anticipate that the personalized glomerulus chip model established in this report could help advance future studies of kidney disease mechanisms and the discovery of personalized therapies. Given the remarkable ability of human iPS cells to differentiate into almost any cell type, this work also provides a blueprint for the establishment of more personalized organ chip and ‘body-on-a-chip’ models in the future.

scholarly journals TMPRSS2 and RNA-dependent RNA polymerase are effective targets of therapeutic intervention for treatment of COVID-19 caused by SARS-CoV-2 variants (B.1.1.7 and B.1.351)

2021 ◽  
Author(s):  
Jihye Lee ◽  
JinAh Lee ◽  
Hyeon Ju Kim ◽  
Meehyun Ko ◽  
Youngmee Jee ◽  
...  
Keyword(s):  
Drug Development ◽  
Rna Polymerase ◽  
Viral Entry ◽  
Drug Repositioning ◽  
Therapeutic Interventions ◽  
Main Concern ◽  
Rna Dependent Rna Polymerase ◽  
Vitro Analysis ◽  
The Uk

SARS-CoV-2 is a causative agent of COVID-19 pandemic and the development of therapeutic interventions is urgently needed. So far, monoclonal antibodies and drug repositioning are the main methods for drug development and this effort was partially successful. Since the beginning of COVID-19 pandemic, the emergence of SARS-CoV-2 variants has been reported in many parts of the world and the main concern is whether the current vaccines and therapeutics are still effective against these variant viruses. The viral entry and viral RNA-dependent RNA polymerase (RdRp) are the main targets of current drug development, thus the inhibitory effects of TMPRSS2 and RdRp inhibitors were compared among the early SARS-CoV-2 isolate (lineage A) and the two recent variants (lineage B.1.1.7 and lineage B.1.351) identified in the UK and South Africa, respectively. Our in vitro analysis of viral replication showed that the drugs targeting TMPRSS2 and RdRp are equally effective against the two variants of concern.

scholarly journals Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology

2021 ◽  
Vol 7 ◽  
Author(s):  
Parisa K. Kargaran ◽  
Diogo Mosqueira ◽  
Tamas Kozicz
Keyword(s):  
Mitochondrial Genome ◽  
Disease Modeling ◽  
Nuclear Genome ◽  
Induced Pluripotent Stem Cell ◽  
Mitochondrial Diseases ◽  
Potential Candidate ◽  
Cellular Models ◽  
Mitochondrial Medicine ◽  
Induced Pluripotent

Mitochondrial medicine is an exciting and rapidly evolving field. While the mitochondrial genome is small and differs from the nuclear genome in that it is circular and free of histones, it has been implicated in neurodegenerative diseases, type 2 diabetes, aging and cardiovascular disorders. Currently, there is a lack of efficient treatments for mitochondrial diseases. This has promoted the need for developing an appropriate platform to investigate and target the mitochondrial genome. However, developing these therapeutics requires a model system that enables rapid and effective studying of potential candidate therapeutics. In the past decade, induced pluripotent stem cells (iPSCs) have become a promising technology for applications in basic science and clinical trials, and have the potential to be transformative for mitochondrial drug development. Engineered iPSC-derived cardiomyocytes (iPSC-CM) offer a unique tool to model mitochondrial disorders. Additionally, these cellular models enable the discovery and testing of novel therapeutics and their impact on pathogenic mtDNA variants and dysfunctional mitochondria. Herein, we review recent advances in iPSC-CM models focused on mitochondrial dysfunction often causing cardiovascular diseases. The importance of mitochondrial disease systems biology coupled with genetically encoded NAD+/NADH sensors is addressed toward developing an in vitro translational approach to establish effective therapies.

scholarly journals Approaches to in vitro tissue regeneration with application for human disease modeling and drug development

2014 ◽  
Vol 19 (6) ◽  
pp. 754-762 ◽  
Author(s):  
Mohammad R. Ebrahimkhani ◽  
Carissa L. Young ◽  
Douglas A. Lauffenburger ◽  
Linda G. Griffith ◽  
Jeffrey T. Borenstein
Keyword(s):  
Drug Development ◽  
Tissue Regeneration ◽  
Human Disease ◽  
Disease Modeling

scholarly journals Three-dimensional, multifunctional neural interfaces for cortical spheroids and engineered assembloids

2021 ◽  
Vol 7 (12) ◽  
pp. eabf9153
Author(s):  
Yoonseok Park ◽  
Colin K. Franz ◽  
Hanjun Ryu ◽  
Haiwen Luan ◽  
Kristen Y. Cotton ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Three Dimensional ◽  
Neural Interfaces ◽  
Biological Research ◽  
Neural Cells ◽  
Complex Architectures ◽  
Complex Features ◽  
The Many ◽  
Living Objects

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms.

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