Closing the ‘phenotype gap’ in precision medicine: improving what we measure to understand complex disease mechanisms

2019 ◽  
Vol 30 (7-8) ◽  
pp. 201-211 ◽  
Author(s):  
Calum A. MacRae
Keyword(s):  
Precision Medicine ◽  
Complex Disease ◽  
Disease Mechanisms

scholarly journals Viral Delivery Systems for CRISPR

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 28 ◽  
Author(s):  
Christine L. Xu ◽  
Merry Z. C. Ruan ◽  
Vinit B. Mahajan ◽  
Stephen H. Tsang
Keyword(s):  
Animal Models ◽  
Precision Medicine ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Treatment Targets ◽  
Disease Mechanisms

The frontiers of precision medicine have been revolutionized by the development of Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR)/Cas9 as an editing tool. CRISPR/Cas9 has been used to develop animal models, understand disease mechanisms, and validate treatment targets. In addition, it is regarded as an effective tool for genome surgery when combined with viral delivery vectors. In this article, we will explore the various viral mechanisms for delivering CRISPR/Cas9 into tissues and cells, as well as the benefits and drawbacks of each method. We will also review the history and recent development of CRISPR and viral vectors and discuss their applications as a powerful tool in furthering our exploration of disease mechanisms and therapies.

scholarly journals Microfluidic organ-on-a-chip model of the outer blood–retinal barrier with clinically relevant read-outs for tissue permeability and vascular structure

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Yusuf B. Arık ◽  
Wesley Buijsman ◽  
Joshua Loessberg-Zahl ◽  
Carlos Cuartas-Vélez ◽  
Colin Veenstra ◽  
...  
Keyword(s):  
Complex Disease ◽  
Vascular Structure ◽  
Blood Retinal Barrier ◽  
Future Studies ◽  
Disease Mechanisms ◽  
Visual Disorders ◽  
Organ On A Chip ◽  
Tissue Permeability

This organ-on-a-chip device of the outer blood retinal barrier will allow future studies of complex disease mechanisms and treatments of visual disorders using clinically relevant endpoints in vitro.

scholarly journals Analysis of Topological Parameters of Complex Disease Genes Reveals the Importance of Location in a Biomolecular Network

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 143 ◽  
Author(s):  
Xiaohui Zhao ◽  
Zhi-Ping Liu
Keyword(s):  
Complex Disease ◽  
Significant Degree ◽  
Clustering Coefficient ◽  
Gene Location ◽  
Disease Genes ◽  
Complex Disorders ◽  
Topological Parameters ◽  
Topological Features ◽  
Disease Mechanisms ◽  
Biomolecular Network

Network biology and medicine provide unprecedented opportunities and challenges for deciphering disease mechanisms from integrative viewpoints. The disease genes and their products perform their dysfunctions via physical and biochemical interactions in the form of a molecular network. The topological parameters of these disease genes in the interactome are of prominent interest to the understanding of their functionality from a systematic perspective. In this work, we provide a systems biology analysis of the topological features of complex disease genes in an integrated biomolecular network. Firstly, we identify the characteristics of four network parameters in the ten most frequently studied disease genes and identify several specific patterns of their topologies. Then, we confirm our findings in the other disease genes of three complex disorders (i.e., Alzheimer’s disease, diabetes mellitus, and hepatocellular carcinoma). The results reveal that the disease genes tend to have a higher betweenness centrality, a smaller average shortest path length, and a smaller clustering coefficient when compared to normal genes, whereas they have no significant degree prominence. The features highlight the importance of gene location in the integrated functional linkages.

scholarly journals Precision medicine in rare disease: Mechanisms of disparate effects of N -carbamyl- l -glutamate on mutant CPS1 enzymes

2017 ◽  
Vol 120 (3) ◽  
pp. 198-206 ◽  
Author(s):  
Dashuang Shi ◽  
Gengxiang Zhao ◽  
Nicholas Ah Mew ◽  
Mendel Tuchman
Keyword(s):  
Precision Medicine ◽  
Rare Disease ◽  
Disease Mechanisms

scholarly journals Science is 1% inspiration and 99% biomarkers

2017 ◽  
Vol 23 (11) ◽  
pp. 1442-1452 ◽  
Author(s):  
Nicolas Dubuisson ◽  
Fabiola Puentes ◽  
Gavin Giovannoni ◽  
Sharmilee Gnanapavan
Keyword(s):  
Multiple Sclerosis ◽  
Complex Disease ◽  
Neurofilament Proteins ◽  
Underlying Process ◽  
Disease Mechanisms ◽  
Bradford Hill ◽  
Bradford Hill Criteria ◽  
Hill Criteria

Neurodegeneration plays a key role in multiple sclerosis (MS) contributing to long-term disability in patients. The prognosis is, however, unpredictable coloured by complex disease mechanisms which can only be clearly appreciated using biomarkers specific to pathobiology of the underlying process. Here, we describe six promising neurodegenerative biomarkers in MS (neurofilament proteins, neurofilament antibodies, tau, N-acetylaspartate, chitinase and chitinase-like proteins and osteopontin), critically evaluating the evidence using a modified Bradford Hill criteria.

scholarly journals Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis

2020 ◽  
Author(s):  
Lingxia Xu ◽  
Shicheng Guo ◽  
Cen Chang ◽  
Runrun Zhang ◽  
Yehua Jin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Histone Modification ◽  
Precision Medicine ◽  
Drug Targets ◽  
Complex Disease ◽  
Immune Cell ◽  
Response Prediction ◽  
Immune Genes ◽  
Environment Exposure

Rheumatoid arthritis (RA) as a complex disease is thought triggered by interaction between genetics and environment, especially the shared epitope (SE) and cell surface calreticulin (CSC) theory. However, all the evidence shows genetic diversity and environment exposure cannot explain all the clinical characteristics heterogeneity of rheumatoid arthritis. In contrast, recent studies demonstrate that epigenetics play important roles in the pathogenesis of rheumatoid arthritis, especially DNA methylation and histone modification. DNA methylation and histone methylation are involved in innate and adoptive immune cell differentiation and the migration, proliferation, apoptosis, and mesenchymal characteristics of fibroblast-like synoviocytes (FLS). Epigenetic mediated regulation to immune genes and inflammation pathway provides well explanation to dynamic expression network of rheumatoid arthritis. In this review, we summarized the comprehensive evidence to show methylation modification occurred in DNA and histone are significantly involved in the pathogenesis of rheumatoid arthritis and could be applied as the promising biomarker in the disease activity and drug response prediction. We also explained the opportunity and challenge of the current epigenetics research in rheumatoid arthritis. In summary, epigenetic modules provide possible interface through which genetic and environmental risk factors connect together to contribute to the susceptibility and pathogenesis of RA. Meanwhile epigenetic regulators provided promising drug targets to develop novel therapeutic drugs for rheumatoid arthritis. Finally, DNA methylation and histone modification will be important features to provide better rheumatoid arthritis subtype identification to accelerate personalized treatment and precision medicine.

scholarly journals Network medicine in Cardiovascular Research

2020 ◽  
Author(s):  
Laurel Y Lee ◽  
Arvind K Pandey ◽  
Bradley A Maron ◽  
Joseph Loscalzo
Keyword(s):  
Cardiovascular Diseases ◽  
Complex Disease ◽  
Clinical Phenotype ◽  
Rational Drug Design ◽  
Integrative Approach ◽  
Network Medicine ◽  
Cardiovascular Research ◽  
Disease Mechanisms ◽  
Rational Drug ◽  
Basic Concepts

Abstract The ability to generate multi-omics data coupled with deeply characterizing the clinical phenotype of individual patients promises to improve understanding of complex cardiovascular pathobiology. There remains an important disconnection between the magnitude and granularity of these data and our ability to improve phenotype–genotype correlations for complex cardiovascular diseases. This shortcoming may be due to limitations associated with traditional reductionist analytical methods, which tend to emphasize a single molecular event in the pathogenesis of diseases more aptly characterized by crosstalk between overlapping molecular pathways. Network medicine is a rapidly growing discipline that considers diseases as the consequences of perturbed interactions between multiple interconnected biological components. This powerful integrative approach has enabled a number of important discoveries in complex disease mechanisms. In this review, we introduce the basic concepts of network medicine and highlight specific examples by which this approach has accelerated cardiovascular research. We also review how network medicine is well-positioned to promote rational drug design for patients with cardiovascular diseases, with particular emphasis on advancing precision medicine.

scholarly journals Modelling Neuromuscular Diseases in the Age of Precision Medicine

2020 ◽  
Vol 10 (4) ◽  
pp. 178
Author(s):  
Alfina A. Speciale ◽  
Ruth Ellerington ◽  
Thomas Goedert ◽  
Carlo Rinaldi
Keyword(s):  
Precision Medicine ◽  
State Of The Art ◽  
Neurological Diseases ◽  
Neuromuscular Diseases ◽  
Therapeutic Approaches ◽  
Current State ◽  
Disease Mechanisms ◽  
Technological Developments ◽  
Clinical Phenotyping

Advances in knowledge resulting from the sequencing of the human genome, coupled with technological developments and a deeper understanding of disease mechanisms of pathogenesis are paving the way for a growing role of precision medicine in the treatment of a number of human conditions. The goal of precision medicine is to identify and deliver effective therapeutic approaches based on patients’ genetic, environmental, and lifestyle factors. With the exception of cancer, neurological diseases provide the most promising opportunity to achieve treatment personalisation, mainly because of accelerated progress in gene discovery, deep clinical phenotyping, and biomarker availability. Developing reproducible, predictable and reliable disease models will be key to the rapid delivery of the anticipated benefits of precision medicine. Here we summarize the current state of the art of preclinical models for neuromuscular diseases, with particular focus on their use and limitations to predict safety and efficacy treatment outcomes in clinical trials.

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