scholarly journals A framework for translation of genomic responses from mouse models to human inflammatory disease contexts

2018 ◽  
Author(s):  
Douglas K. Brubaker ◽  
Elizabeth A. Proctor ◽  
Kevin M. Haigis ◽  
Douglas A. Lauffenburger
Keyword(s):  
Neural Network ◽  
Artificial Neural Network ◽  
Mouse Model ◽  
Mouse Models ◽  
Differentially Expressed Genes ◽  
Inflammatory Disease ◽  
Human Disease ◽  
Model Systems ◽  
Learning Approach

ABSTRACTThe high failure rate of therapeutics showing promise in mouse disease models to translate to patients is a pressing challenge in biomedical science. However, mouse models are a useful tool for evaluating mechanisms of disease and prioritizing novel therapeutic agents for clinical trials. Though retrospective studies have examined the fidelity of mouse models of inflammatory disease to their respective human in vivo conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for prospective inference of disease-associated human in vivo differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human in vivo biology from mouse model datasets. We found that a semi-supervised artificial neural network identified significantly more true human in vivo associations than interpreting mouse experiments directly (95% CI on F-score for mouse experiments [0.090, 0.175], neural network [0.278, 0.375], p = 0.00013). Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches combining mouse and human data for biological inference provides the most accurate assessment of human in vivo disease and therapeutic mechanisms. The task of translating insights from model systems to human disease contexts may therefore be better accomplished by the use of systems modeling driven approaches.Author SummaryComparison of genomic responses in mouse models and human disease contexts is not sufficient for addressing the challenge of prospective translation from mouse models to human disease contexts. Here, we address this challenge by developing a semi-supervised machine learning approach that combines supervised modeling of mouse experiment datasets with unsupervised modeling of human disease-context datasets to predict human in vivo differentially expressed genes and pathways as if the model system experiment had been run in the human cohort. A semi-supervised version of a feed forward artificial neural network was the most efficacious model for translating experimentally derived mouse molecule-phenotype associations to the human in vivo disease context. We find that computational generalization of signaling insights from mouse to human contexts substantially improves upon direct generalization of mouse experimental insights and argue that such approaches can facilitate more clinically impactful translation of insights from preclinical studies in model systems to patients.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Mouse models of human cancer and the need for more translational research

2008 ◽  
Author(s):  
Martin Fenner
Keyword(s):  
Mouse Model ◽  
Translational Research ◽  
Synovial Sarcoma ◽  
Mouse Models ◽  
Human Disease ◽  
Human Cancer ◽  
Neuropsychiatric Disorders ◽  
International Congress

One of the opening lectures this Saturday of the International Congress of Genetics was held by Mario Capecchi. His talked was entitled Modeling human disease in the mouse: from cancer to neuropsychiatric disorders. In the first half he described his mouse model of synovial sarcoma. ...

scholarly journals A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function

2017 ◽  
Vol 118 (2) ◽  
pp. 845-854 ◽  
Author(s):  
Neal S. Peachey ◽  
Nazarul Hasan ◽  
Bernard FitzMaurice ◽  
Samantha Burrill ◽  
Gobinda Pangeni ◽  
...  
Keyword(s):  
Mouse Model ◽  
Missense Mutation ◽  
Mouse Models ◽  
Human Disease ◽  
Bipolar Cell ◽  
Night Blindness ◽  
Cell Function ◽  
Congenital Stationary Night Blindness ◽  
Depolarizing Bipolar Cell

This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a phenotype distinct from that seen in other Grm6 mouse models.

scholarly journals Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0249841
Author(s):  
Ravindra Jadhav ◽  
Ricardo Gallardo-Macias ◽  
Gaurav Kumar ◽  
Samer S. Daher ◽  
Amit Kaushik ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Small Molecules ◽  
Lessons Learned ◽  
Learning Approach ◽  
Mycobacterium Tuberculosis Infection ◽  
Pharmacokinetic Profiles ◽  
Machine Learning Approach ◽  
Selection Of

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

scholarly journals An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models

2022 ◽  
Vol 9 ◽  
Author(s):  
Timothy J. Hines ◽  
Cathleen Lutz ◽  
Stephen A. Murray ◽  
Robert W. Burgess
Keyword(s):  
Human Disease ◽  
Neuromuscular Diseases ◽  
Trna Synthetase ◽  
Genetically Engineered ◽  
Model Systems ◽  
Model Organisms ◽  
Cellular Mechanisms ◽  
Disease Mechanisms

As sequencing technology improves, the identification of new disease-associated genes and new alleles of known genes is rapidly increasing our understanding of the genetic underpinnings of rare diseases, including neuromuscular diseases. However, precisely because these disorders are rare and often heterogeneous, they are difficult to study in patient populations. In parallel, our ability to engineer the genomes of model organisms, such as mice or rats, has gotten increasingly efficient through techniques such as CRISPR/Cas9 genome editing, allowing the creation of precision human disease models. Such in vivo model systems provide an efficient means for exploring disease mechanisms and identifying therapeutic strategies. Furthermore, animal models provide a platform for preclinical studies to test the efficacy of those strategies. Determining whether the same mechanisms are involved in the human disease and confirming relevant parameters for treatment ideally involves a human experimental system. One system currently being used is induced pluripotent stem cells (iPSCs), which can then be differentiated into the relevant cell type(s) for in vitro confirmation of disease mechanisms and variables such as target engagement. Here we provide a demonstration of these approaches using the example of tRNA-synthetase-associated inherited peripheral neuropathies, rare forms of Charcot-Marie-Tooth disease (CMT). Mouse models have led to a better understanding of both the genetic and cellular mechanisms underlying the disease. To determine if the mechanisms are similar in human cells, we will use genetically engineered iPSC-based models. This will allow comparisons of different CMT-associated GARS alleles in the same genetic background, reducing the variability found between patient samples and simplifying the availability of cell-based models for a rare disease. The necessity of integrating mouse and human models, strategies for accomplishing this integration, and the challenges of doing it at scale are discussed using recently published work detailing the cellular mechanisms underlying GARS-associated CMT as a framework.

scholarly journals Tick-Borne Encephalitis Virus Vaccine-Induced Human Antibodies Mediate Negligible Enhancement of Zika Virus Infection In Vitro and in a Mouse Model

mSphere ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
James Duehr ◽  
Silviana Lee ◽  
Gursewak Singh ◽  
Gregory A. Foster ◽  
David Krysztof ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dengue Virus ◽  
Human Plasma ◽  
Mouse Models ◽  
Zika Virus ◽  
Encephalitis Virus ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

ABSTRACT Recent reports in the scientific literature have suggested that anti-dengue virus (DENV) and anti-West Nile virus (WNV) immunity exacerbates Zika virus (ZIKV) pathogenesis in vitro and in vivo in mouse models. Large populations of immune individuals exist for a related flavivirus (tick-borne encephalitis virus [TBEV]), due to large-scale vaccination campaigns and endemic circulation throughout most of northern Europe and the southern Russian Federation. As a result, the question of whether anti-TBEV immunity can affect Zika virus pathogenesis is a pertinent one. For this study, we obtained 50 serum samples from individuals vaccinated with the TBEV vaccine FSME-IMMUN (Central European/Neudörfl strain) and evaluated their enhancement capacity in vitro using K562 human myeloid cells expressing CD32 and in vivo using a mouse model of ZIKV pathogenesis. Among the 50 TBEV vaccinee samples evaluated, 29 had detectable reactivity against ZIKV envelope (E) protein by enzyme-linked immunosorbent assay (ELISA), and 36 showed enhancement of ZIKV infection in vitro. A pool of the most highly reacting and enhanced samples resulted in no significant change in the morbidity/mortality of ZIKV disease in immunocompromised Stat2−/− mice. Our results suggest that humoral immunity against TBEV is unlikely to enhance Zika virus pathogenesis in humans. No clinical reports indicating that TBEV vaccinees experiencing enhanced ZIKV disease have been published so far, and though the epidemiological data are sparse, our findings suggest that there is little reason for concern. This study also displays a clear relationship between the phylogenetic distance between two flaviviruses and their capacity for pathogenic enhancement. IMPORTANCE The relationship between serial infections of two different serotypes of dengue virus and more severe disease courses is well-documented in the literature, driven by so-called antibody-dependent enhancement (ADE). Recently, studies have shown the possibility of ADE in cells exposed to anti-DENV human plasma and then infected with ZIKV and also in mouse models of ZIKV pathogenesis after passive transfer of anti-DENV human plasma. In this study, we evaluated the extent to which this phenomenon occurs using sera from individuals immunized against tick-borne encephalitis virus (TBEV). This is highly relevant, since large proportions of the European population are vaccinated against TBEV or otherwise seropositive.

scholarly journals A Novel BCL2-Driven Compound Mutant Mouse Model for In Vivo Research on BH3 Mimetics

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Ismini Halmer ◽  
Alexandra da Palma Guerreiro ◽  
Laura Beckmann ◽  
Christian Reinhardt ◽  
Hamid Kashkar ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cells ◽  
Mouse Model ◽  
Mouse Models ◽  
Clinical Symptoms ◽  
Conflicts Of Interest ◽  
Bh3 Mimetics ◽  
Normal Ranges

Introduction: Eµ-TCL1-transgenic mouse models are often applied to discover and observe the development and kinetic of chronic lymphocytic leukaemia (CLL), as they develop diseases most similar to human CLL with a very high penetrance. To gain a better understanding on new therapy options and their effect on disease regression it is very important to observe therapy response, overall survival and symptoms during treatment of the disease not only in vitro but also in vivo in a suitable mouse model. However, application of BH3 mimetics like venetoclax is limited in the classical Eµ-TCL1 mouse model, since these mice are resistant towards venetoclax treatment. Therefore, we have generated a novel mouse model with Eµ-TCL1 as back bone and conditional overexpression of BCL2. Methods and results: We established a new mouse model (TBC) by crossbreeding mice expressing Eµ-TCL1tg/wtwith mice containing a B-cell specific conditional Bcl-2Rosa26/wt; Cd19CreCre/wtoverexpression and compared the disease kinetics to classical Eµ-TCL1 mice and to BC mice. TBC animals exhibit a severe leukocytosis at very early stages of disease development (12 weeks; mean 96.000/µl) in comparison to TC (15.100/µl) and BC (81.900/µl) mice. TBC mice develop CD23low/CD21neg leukemic B cells as they are known from TC mice with CD19+/CD5+ expression. Indeed, these mice show a significantly shortened overall survival of ~300 days (n=43) compared to TC mice (n=106; ~350 days; p<0.001) and BC mice (n=28; ~410 days; p<0.001) with severe clinical symptoms such as splenomegaly and cachexia. Strikingly, in contrast classical TC mice, which are resistant towards venetoclax, isolated B-cells of TBC mice are 10-times more sensitive towards venetoclax in vitro (0,02 µM) and can also be killed by the MCL1 inhibitors in nanomolar ranges, but not by BCL-xl inhibitors (>2µM). Based on our in vitro data, we have treated TBC mice with venetoclax and observed an early and dramatic drop of leukocytes to normal ranges within the first two weeks of treatment. Leukocyte reduction lasted for the whole period of treatment. When investigating the spleens after sacrificing the mice they showed high amounts of dead cells inside the spleens, indicating that venetoclax was also efficient in lymphatic tissues as we know it from human trials. Conclusions: Autochthonous mouse models on which BH3 mimetics can be tested are rare. In our mouse model apoptosis screening in vitro we can show good results for BH3 mimetics with a high sensitivity already in low dosing. The BCL2-driven TCL1 mouse model enables the investigation of treatment with venetoclax in vivo to gain a better understanding of this frequently on patients applied therapy. Moreover, this model will help us to test other drugs (like MCL1 inhibitors) in combination with venetoclax to identify synergistic drugs in vivo in a timely manner. Furthermore, this model will offer us the opportunity to identify treatment strategies to overcome venetoclax resistance in vivo. Disclosures No relevant conflicts of interest to declare.

scholarly journals Saturation mutagenesis defines novel mouse models of severe spine deformity

2021 ◽  
Author(s):  
Jonathan J Rios ◽  
Kristin Denton ◽  
Hao Yu ◽  
Kandamurugu Manickam ◽  
Shannon Garner ◽  
...  
Keyword(s):  
Mouse Models ◽  
Human Disease ◽  
Spinal Column ◽  
Saturation Mutagenesis ◽  
Recessive Mutation ◽  
Spine Deformity ◽  
Skeletal Disease ◽  
Genetic Mouse Models

Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of the skeletal, muscular, and nervous systems, which may result in deformities such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1,275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1,275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated ENU alleles in 21% of pedigrees. Our study provides proof-of-concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural, and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced trans-activation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.

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