scholarly journals Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

2021 ◽  
Vol 22 (4) ◽  
pp. 1954
Author(s):  
Sara H. Osum ◽  
Adrienne L. Watson ◽  
David A. Largaespada
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Mouse Models ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Genetically Engineered ◽  
Large Animal ◽  
Large Animal Models ◽  
Naturally Occurring

Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients.

scholarly journals TMOD-23. PRECLINICAL DRUG EVALUATION IN A GENETICALLY ENGINEERED MINIPIG MODEL OF NEUROFIBROMATOSIS TYPE 1

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi267-vi267
Author(s):  
Sara Osum ◽  
Anat Stemmer-Rachamimov ◽  
Brigitte Widemann ◽  
Eva Dombi ◽  
Jeremie Vitte ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Model ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
New Drugs ◽  
Optic Pathway Glioma ◽  
Large Animal ◽  
Safety And Efficacy ◽  
Mek Inhibitors

Abstract We have employed gene-editing technology to create a Neurofibromatosis Type 1 (NF1) minipig that replicates the broad spectrum of disease that develops in NF1 patients and meets the National Institute of Health’s diagnostic criteria for NF1. The NF1 boars are fertile and the NF1 mutant allele is transmitted at a Mendelian rate with no reduction in fitness of offspring that inherit this allele. To date, we have observed 100% penetrance of café au lait macules, a phenotype that occurs in nearly every NF1 patient, but has never been demonstrated in any other animal model. The NF1 minipig develops cutaneous neurofibromas and optic pathway glioma, that histologically resemble human tumors. Additionally, we have observed other NF1-associated phenotypes including Lisch nodules, tibial dysplasia, white matter decompaction, hypopigmentation, and freckling of the skin. The FDA has emphasized the need for development and testing of new therapies in large animal disease models prior to human studies. Therefore, we have conducted pharmacological studies in our NF1 swine to look at the pharmacokinetic and pharmacodynamic properties MEK inhibitors, currently in clinical trials for NF1. We have demonstrated that oral administration of the MEK inhibitors results in clinically relevant plasma levels of the drug and inhibition of Ras signaling, and that certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. We envision this large animal model of NF1 will become a standard in the evaluation of the safety and efficacy of new drugs prior to Phase I clinical trials. Further, an NF1 minipig may enable researchers to better understand the biological and genetic mechanisms underlying this complex disease, detect NF1-related tumors earlier, identify biomarkers, discover novel drug targets, and test new drugs and combination therapies for safety and efficacy.

scholarly journals Characterization of early communicative behavior in mouse models of neurofibromatosis type 1

2017 ◽  
Vol 11 (1) ◽  
pp. 44-58 ◽  
Author(s):  
Susan E. Maloney ◽  
Krystal C. Chandler ◽  
Corina Anastasaki ◽  
Michael A. Rieger ◽  
David H. Gutmann ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Communicative Behavior

scholarly journals Spontaneous and Induced Animal Models for Cancer Research

Diagnostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 660
Author(s):  
Anca Onaciu ◽  
Raluca Munteanu ◽  
Vlad Cristian Munteanu ◽  
Diana Gulei ◽  
Lajos Raduly ◽  
...  
Keyword(s):  
Cancer Research ◽  
Animal Models ◽  
Mouse Models ◽  
Behavioral Science ◽  
Laboratory Mouse ◽  
Human Tumor ◽  
Large Animal ◽  
Large Animal Models ◽  
Oncology Research ◽  
Genetically Engineered Mice

Considering the complexity of the current framework in oncology, the relevance of animal models in biomedical research is critical in light of the capacity to produce valuable data with clinical translation. The laboratory mouse is the most common animal model used in cancer research due to its high adaptation to different environments, genetic variability, and physiological similarities with humans. Beginning with spontaneous mutations arising in mice colonies that allow for pursuing studies of specific pathological conditions, this area of in vivo research has significantly evolved, now capable of generating humanized mice models encompassing the human immune system in biological correlation with human tumor xenografts. Moreover, the era of genetic engineering, especially of the hijacking CRISPR/Cas9 technique, offers powerful tools in designing and developing various mouse strains. Within this article, we will cover the principal mouse models used in oncology research, beginning with behavioral science of animals vs. humans, and continuing on with genetically engineered mice, microsurgical-induced cancer models, and avatar mouse models for personalized cancer therapy. Moreover, the area of spontaneous large animal models for cancer research will be briefly presented.

Immune Relevant Models for Ocular Inflammatory Diseases

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 352-362 ◽  
Author(s):  
Brian C Gilger
Keyword(s):  
Animal Models ◽  
Dry Eye ◽  
Vision Loss ◽  
Inflammatory Diseases ◽  
Ocular Inflammation ◽  
Ocular Disease ◽  
Large Animal ◽  
Antiinflammatory Drugs ◽  
Large Animal Models ◽  
Naturally Occurring

AbstractOcular inflammatory diseases, such as dry eye and uveitis, are common, painful, difficult to treat, and may result in vision loss or blindness. Ocular side effects from the use of antiinflammatory drugs (such as corticosteroids or nonsteroidal antiinflammatories) to treat ocular inflammation have prompted development of more specific and safer medications to treat inflammatory and immune-mediated diseases of the eye. To assess the efficacy and safety of these new therapeutics, appropriate immune-relevant animal models of ocular inflammation are needed. Both induced and naturally-occurring models have been described, but the most valuable for translating treatments to the human eye are the animal models of spontaneous, immunologic ocular disease, such as those with dry eye or uveitis. The purpose of this review is to describe common immune-relevant models of dry eye and uveitis with an overview of the immuno-pathogenesis of each disease and reported evaluation of models from small to large animals. We will also review a selected group of naturally-occurring large animal models, equine uveitis and canine dry eye, that have promise to translate into a better understanding and treatment of clinical immune-relevant ocular disease in man.

scholarly journals Clinical trial design in neurofibromatosis type 1 as a model for other tumor predisposition syndromes

2020 ◽  
Vol 2 (Supplement_1) ◽  
pp. i134-i140
Author(s):  
Andrea M Gross ◽  
Brigitte C Widemann
Keyword(s):  
Clinical Trials ◽  
Neurofibromatosis Type 1 ◽  
Clinical Trial Design ◽  
Neurofibromatosis Type ◽  
Lessons Learned ◽  
Benign Tumors ◽  
Pediatric Cancer Patients ◽  
Patient Reported ◽  
Trial Endpoints

Abstract Up to 10% of all pediatric cancer patients may have an underlying germline mutation which predisposed them to develop a malignancy. With more patients being tested for and diagnosed with genetic tumor predisposition syndromes, there has been improved characterization of their many nonmalignant manifestations. However, designing and implementing clinical trials to treat the nonmalignant tumor and non-tumor manifestations of these syndromes poses many unique challenges. Unlike trials for malignancies where tumor response and survival can be used as straightforward trial endpoints, the nonmalignant manifestations are often chronic, evolve more slowly over time, and may not be immediately life-threatening. Therefore, they will likely require a different approach to both testing and treatment with a focus on more functional and patient-reported outcome trial endpoints. The recent success of treatment trials for the benign tumors plexiform neurofibromas in the tumor predisposition syndrome neurofibromatosis type 1 (NF1) can be used as a model for the development of clinical trials in other tumor predisposition syndromes. In this article, we review the unique challenges associated with targeting the nonmalignant aspects of these conditions as well as some of the lessons learned from the NF1 experience which may be applied to other syndromes in the future.

scholarly journals Adult Canine Intestinal Derived Organoids: A Novel In Vitro System for Translational Research in Comparative Gastroenterology

2018 ◽  
Author(s):  
Lawrance Chandra ◽  
Dana C Borcherding ◽  
Dawn Kingsbury ◽  
Todd Atherly ◽  
Yoko M Ambrosini ◽  
...  
Keyword(s):  
Animal Models ◽  
Translational Research ◽  
Three Dimensional ◽  
Metabolic Imaging ◽  
Large Animal ◽  
Large Animal Models ◽  
Molecular Features ◽  
Naturally Occurring

AbstractBackgroundLarge animal models, such as the dog, are increasingly being used over rodent models for studying naturally occurring diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between currently used animal models (e.g. mouse) and humans, and expand the translational potential of the dog model, we developed a three dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.ResultsOrganoids were propagated from isolation of adult intestinal stem cells (ISC) from whole jejunal tissue as well as endoscopically obtained duodenal, ileal and colonic biopsy samples of healthy dogs and GI cases, including inflammatory bowel disease (IBD) and intestinal carcinomas. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization and transmission electron microscopy, and organoids mimicked the in vivo tissue environment. Physiological relevance of the enteroid system was defined using functional assays such as Optical Metabolic Imaging (OMI), the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research.ConclusionsIn summary, our findings establish the canine GI organoid systems as a novel model to study naturally occurring intestinal diseases in dogs and humans. Furthermore, canine organoid systems will help to elucidate host-pathogen interactions contributing to GI disease pathogenesis.

scholarly journals REiNS: Recommendations for Social Skills Endpoints for Clinical Trials in Neurofibromatosis Type 1

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012422
Author(s):  
Jennifer A. Janusz ◽  
Bonita P. Klein-Tasman ◽  
Jonathan M. Payne ◽  
Pamela L. Wolters ◽  
Heather L. Thompson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Social Skills ◽  
Social Functioning ◽  
Neurofibromatosis Type 1 ◽  
Rating Scale ◽  
Neurofibromatosis Type ◽  
Autism Spectrum ◽  
The Social ◽  
Two Measures

Objective:We reviewed parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with Neurofibromatosis Type 1 (NF1).Method:Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials.Results:Two measures were ultimately recommended by the committee – the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System- Rating Scale (SSIS-RS).Conclusions:Each of the two measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning, while the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

scholarly journals A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

2021 ◽  
Vol 22 (23) ◽  
pp. 13168
Author(s):  
Natasha Elizabeth Mckean ◽  
Renee Robyn Handley ◽  
Russell Grant Snell
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Mouse Model ◽  
Mouse Models ◽  
Small Animal ◽  
Large Animal ◽  
Complex Disorders ◽  
Large Animal Models ◽  
The Impact

Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes.

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