scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Coculture with hiPS-derived intestinal cells enhanced human hepatocyte functions in a pneumatic-pressure-driven two-organ microphysiological system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie Shinohara ◽  
Hiroshi Arakawa ◽  
Yuuichi Oda ◽  
Nobuaki Shiraki ◽  
Shinji Sugiura ◽  
...  
Keyword(s):  
Normal Cell ◽  
Human Hepatocytes ◽  
New Drugs ◽  
Intestinal Cells ◽  
Specific Gene ◽  
Gene Expressions ◽  
Normal Cells ◽  
Pneumatic Pressure ◽  
Pressure Driven

AbstractExamining intestine–liver interactions is important for achieving the desired physiological drug absorption and metabolism response in in vitro drug tests. Multi-organ microphysiological systems (MPSs) constitute promising tools for evaluating inter-organ interactions in vitro. For coculture on MPSs, normal cells are challenging to use because they require complex maintenance and careful handling. Herein, we demonstrated the potential of coculturing normal cells on MPSs in the evaluation of intestine–liver interactions. To this end, we cocultured human-induced pluripotent stem cell-derived intestinal cells and fresh human hepatocytes which were isolated from PXB mice with medium circulation in a pneumatic-pressure-driven MPS with pipette-friendly liquid-handling options. The cytochrome activity, albumin production, and liver-specific gene expressions in human hepatocytes freshly isolated from a PXB mouse were significantly upregulated via coculture with hiPS-intestinal cells. Our normal cell coculture shows the effects of the interactions between the intestine and liver that may occur in vivo. This study is the first to demonstrate the coculturing of hiPS-intestinal cells and fresh human hepatocytes on an MPS for examining pure inter-organ interactions. Normal-cell coculture using the multi-organ MPS could be pursued to explore unknown physiological mechanisms of inter-organ interactions in vitro and investigate the physiological response of new drugs.

scholarly journals Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1647
Author(s):  
Keishi Kisoh ◽  
Go Sugahara ◽  
Yuko Ogawa ◽  
Suzue Furukawa ◽  
Yuji Ishida ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Efficacy ◽  
Developed Countries ◽  
Liver Disorder ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Chimeric Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Nash Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

scholarly journals A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box

2018 ◽  
Vol 62 (4) ◽  
pp. e01505-17 ◽  
Author(s):  
R. S. Jumani ◽  
K. Bessoff ◽  
M. S. Love ◽  
P. Miller ◽  
E. E. Stebbins ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Early Stage ◽  
New Drugs ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Knockout Mouse Model ◽  
Malaria Box

ABSTRACTCryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies,in vitrotoxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound againstCryptosporidium parvumIowa and field isolates was comparable to that againstCryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads and may aid in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

Human hepatocytes as a keyin vitro model to improve preclinical drug development

1990 ◽  
Vol 15 (2) ◽  
pp. 165-171 ◽  
Author(s):  
Gerard Fabre ◽  
Jean Combalbert ◽  
Yves Berger ◽  
Jean -Paul Cano
Keyword(s):  
Drug Development ◽  
Human Hepatocytes ◽  
Preclinical Drug Development ◽  
Vitro Model

scholarly journals FBDD: In-silico STRATEGY TO INHIBIT MPRO ACTIVITY USING DRUGS FROM PREVIOUS OUTBREAKS

2021 ◽  
Vol 9 (4) ◽  
pp. 472-480
Author(s):  
Gauravi N Trivedi ◽  
◽  
Janhavi T Karlekar ◽  
Khushbu Dhimmar ◽  
Hetal kumar Panchal ◽  
...  
Keyword(s):  
Drug Development ◽  
In Silico ◽  
Drug Targets ◽  
Transmission Rate ◽  
Respiratory Illness ◽  
Primary Treatment ◽  
Rational Drug Design ◽  
New Drugs ◽  
Main Protease

Main protease (Mpro) and Spike (S) proteins are said potential drug targets of COVID-19. Pneumonia like respiratory illness caused by SARS-CoV-2 is spreading rapidly due to its replication and transmission rate. Protease is the protein that is involved in both replication and transcription. Since CoV-2 shares, genomic similarity with CoV and MERS-CoV, drugs from previous outbreaks are used as primary treatment of the disease. In-silico drug development strategies are said to be faster and effective than in-vitro with a lesser amount of risk factors. Fragment Based Drug Designing (FBDD), also known as rational drug design in which a potential target protein is selected and docked with a lead-like molecule that eventually leads to drug development. Nine (9) drugs that are currently being used to treat patients of coronavirus were selected in this study from the latest literature review and fragmented as per rules followed by crosslinking of drug fragments using editor tools. These native drugs and synthesized drugs were then docked against the main protease. Results of the study revealed that one of the crosslinked lead-like compounds showed a higher binding affinity (∆G) more than any of the native compounds. Further, the results of this study suggested that the combination of potential drugs can be an effective way to develop new drugs to treat a deadly disease.

scholarly journals Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

2021 ◽  
Vol 83 (10) ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark A. J. Chaplain ◽  
Gibin G. Powathil
Keyword(s):  
Dna Damage ◽  
Drug Development ◽  
Agent Based Model ◽  
Agent Based ◽  
Preclinical Drug Development ◽  
Dna Damage Responses ◽  
Treatment Responses ◽  
Cellular Dna

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

Sign in / Sign up

Export Citation Format

Share Document