Potential candidate genomic biomarkers of drug induced vascular injury in the rat

Dalmas, Deidre A.; Scicchitano, Marshall S.; Mullins, David W.; Hughes‐Earle, Angela; Tatsuoka, Kay; Magid-Slav, Michal; Frazier, Kendall S.; Thomas, Heath C.

doi:10.1016/j.taap.2011.09.015

Cited by 21 publications

(43 citation statements)

References 33 publications

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“…Although we did not validate the translational statin response in the in vivo cynomolgus macaque because of time and cost constraints, we did perform a similar study where we validated the translation drug response of fenoldopam in rats with our rat vascular surrogate system and demonstrated similar responses. [44][45][46] Finally, we have found that certain biological pathways that may explain statin effects on other tissues, such as skeletal muscle, are conserved in our vascular tissue. Thus, many of the effects observed in the vascular system potentially may be translated to other organ systems.…”

Section: Table 3 Summary Of Gene Mutations That Lead To Muscle Pathomentioning

confidence: 98%

An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation

Cole¹,

Simmers²,

Feaver³

et al. 2015

ATVB

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Cynomolgus macaques are highly responsive to atherogenic diets, and the atherogenic response is influenced by lipoprotein diet composition. Atherogenic diet-fed cynomolgus macaques develop coronary artery lesions, raised plasma cholesterol levels, and lesions of similar composition to humans. Atherosclerosis development in cynomolgus macaques is highly influenced by genetic predisposition, confounding diseases (such as diabetes mellitus), exercise, sex (increased susceptibility in men), and behavioral and psychosocial factors. Objectives-The predictive value of animal and in vitro systems for drug development is limited, particularly for nonhuman primate studies as it is difficult to deduce the drug mechanism of action. We describe the development of an in vitro cynomolgus macaque vascular system that reflects the in vivo biology of healthy, atheroprone, or advanced inflammatory cardiovascular disease conditions. Approach and Results-We compare the responses of the in vitro human and cynomolgus vascular systems to 4 statins.Although statins exert beneficial pleiotropic effects on the human vasculature, the mechanism of action is difficult to investigate at the tissue level. Using RNA sequencing, we quantified the response to statins and report that most statins significantly increased the expression of genes that promote vascular health while suppressing inflammatory cytokine gene expression. Applying computational pathway analytics, we identified statin-regulated biological themes, independent of cholesterol lowering, that provide mechanisms for off-target effects, including thrombosis, cell cycle regulation, glycogen metabolism, and ethanol degradation. Conclusions-The cynomolgus vascular system described herein mimics the baseline and inflammatory regional biology of the human vasculature, including statin responsiveness, and provides mechanistic insight not achievable in vivo. All of these characteristics are similar to the human atherosclerosis disease, and thus, they make cynomolgus macaques a good nonhuman primate model for atherosclerosis. 7,8 In this study, a cynomolgus vascular system was developed using primary endothelial cells (ECs), smooth muscle cells (SMCs), and hemodynamics derived in vivo from cynomolgus arteries. The system was validated against inflammatory risk factor response, including a comparison between human-and cynomolgus-derived oxidized low-density lipoproteins (LDLs), and exposure to several statins. A comparative analysis between the cynomolgus and human vascular tissue systems was conducted to determine the cross-species translational capabilities of these models, which is an important component in the transition from preclinical to human clinical studies. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Development of an In Vitro Cynomolgus Vascular Surrogate SystemThe human vascular surrogate system applies human-derived blood shear stress patterns to a transwell vascular coculture of ECs and SMCs ( Figure 1A). Atherosclerotic...

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Section: Table 3 Summary Of Gene Mutations That Lead To Muscle Pathomentioning

confidence: 98%

An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation

Cole¹,

Simmers²,

Feaver³

et al. 2015

ATVB

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“…[5] There have been numerous publications demonstrating promise of TGx for more accurate and/or earlier prediction of toxicity outcomes such as vascular injury and carcinogenicity. [1,[6][7][8] [9] TGx has also contributed to the mechanistic understanding of some toxicity issues, for example, explaining rodent-specific carcinogenesis associated with peroxisome proliferator-activated receptor α agonists. [10] However, TGx has not been widely incorporated into drug discovery pipelines.…”

Section: The Advance Of Toxicogenomicsmentioning

confidence: 99%

Toxicogenomics in drug development: a match made in heaven?

Qin

Tanis

Podtelezhnikov

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Although further validation still is required to qualify genomic candidate tissue markers, a gene panel now is available to aid in the prediction and identification of mesenteric DIVI in the rat (Dalmas et al 2008;Dalmas et al 2011). This gene list provides an opportunity to identify additional circulating proteomic biomarkers of DIVI, because several of these genes correspond to secreted proteins.…”

Section: Gene Panel Predictivitymentioning

confidence: 99%

Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

et al. 2014

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Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI.

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Potential candidate genomic biomarkers of drug induced vascular injury in the rat

Cited by 21 publications

References 33 publications

An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation

An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation

Toxicogenomics in drug development: a match made in heaven?

Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

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