Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysms

Hansen, Jens; Galatioto, Josephine; Caescu, Cristina I.; Arnaud, Pauline; Calizo, Rhodora C.; Spronck, Bart; Murtada, Sae‐Il; Borkar, Roshan M.; Weinberg, Alan; Azeloglu, Evren U.; Bintanel-Morcillo, María; Gallo, James M.; Humphrey, Jay D.; Jondeau, Guillaume; Boileau, Cathérine; Ramirez, Francesco; Iyengar, Ravi

doi:10.1172/jci.insight.127652

Cited by 26 publications

(47 citation statements)

References 48 publications

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“…Competent elastic fibers endow the aortic wall with an ability to store energy elastically during systole, which can then be used to work on the blood during diastole to augment flow, as, for example, to perfuse the coronary arteries of the left heart. Most histopathological studies reveal local fragmentation or loss of elastic fibers in human and murine TAAs (e.g., [ 14 , 51 ]). Figs 1 and 2 (first rows) show predicted results for locally compromised elastic fiber integrity both without and with the added risk factors of hypertension and aortic aging–these figures show the mechanically-loaded geometry after the lesion has developed, with colorimetric scaling for elastic energy storage ( Fig 1 ) and circumferential material stiffness ( Fig 2 ).…”

Section: Resultsmentioning

confidence: 99%

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Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Latorre

Humphrey

2020

PLoS Comput Biol

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Myriad risk factors–including uncontrolled hypertension, aging, and diverse genetic mutations–contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.

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Section: Resultsmentioning

confidence: 99%

“…[ 11 , 12 ]). Indeed, genetic analyses reveal hundreds of differentially expressed genes even in the case of a targeted mutation to a single gene (e.g., [ 13 , 14 ]), suggesting that additional collateral or compensatory changes can complicate interpretation further.…”

Section: Introductionmentioning

confidence: 99%

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Latorre

Humphrey

2020

PLoS Comput Biol

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“…RNA libraries were sequenced on the Illumina HiSeq 2000 System with 100 nucleotide single-end reads, according to the standard manufacturer’s protocol (Illumina). For RNA-seq data analysis, Star 2.5.4b and bowtie2 2.1.0, samtools 0.1.7, and cufflinks 1.3.0 were used as described previously ( Stillitano et al, 2017 ; Hansen et al, 2019 ; Mariottini et al, 2019 ). Before read alignment, we identified the sample with the lowest read counts (16,726,861 reads) and down-sampled all other samples to the same number of read counts by randomly removing excessive reads ( Supplementary Figure 4A ) to prevent distortion of RNA-seq results by read count imbalances, as described previously ( Stillitano et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice

Toro

Hansen

Siddiq

et al. 2021

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

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“…A recent preclinical in vivo study identified the GABA B receptor agonist baclofen as a possible therapeutic drug to treat muscle contractility defects, which contribute to aortic aneurysm development in MFS. 213 Using transcriptomic data from both Fbn1 mgR/mgR MFS mouse (on a pure C57BL/6 background) and human MFS aortic samples, reduced muscle contractility was identified as a common affected subcellular pathway, with baclofen as a predicted treatment to correct the dysregulated transcription profile. Treatment of Fbn1 mgR/mgR mice with baclofen indeed demonstrated a reduced aneurysm growth rate, resulting in a significant extension of the median survival rate.…”

Section: Experimental Treatments Tested In Preclinical Studiesmentioning

confidence: 99%

“…Hansen et al used an unbiased approach to identify potential biological treatment targets using computation analysis of transcriptomic data derived from both pre-clinical experiments and from clinical trials. 213 The goal was to investigate common subcellular pathways involved in MFS pathology and use this information to predict the potential efficacy of repurposed FDA-approved drugs for treating the disease. This approach has already successfully led to the identification of the GABA B receptor as a potential therapeutic target, and might uncover more novel mechanisms in the future.…”

Section: Current Challenges and Future Directionsmentioning

confidence: 99%

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

Deleeuw¹,

Clercq²,

Backer³

et al. 2021

JEP

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Marfan syndrome (MFS) is a heritable connective tissue disorder caused by pathogenic variants in the gene coding for the extracellular matrix protein fibrillin-1. While the disease affects multiple organ systems, the most life-threatening manifestations are aortic aneurysms leading to dissection and rupture. Other cardiovascular complications, including mitral valve prolapse, primary cardiomyopathy, and arrhythmia, also occur more frequently in patients with MFS. The standard medical care relies on cardiovascular imaging at regular intervals, along with pharmacological treatment with β-adrenergic receptor blockers aimed at reducing the aortic growth rate. When aortic dilatation reaches a threshold associated with increased risk of dissection, prophylactic surgical aortic replacement is performed. Although current clinical management has significantly improved the life expectancy of patients with MFS, no cure is available and fatal complications still occur, underscoring the need for new treatment options. In recent years, preclinical studies have identified a number of potentially promising therapeutic targets. Nevertheless, the translation of these results into clinical practice has remained challenging. In this review, we present an overview of the currently available knowledge regarding the underlying pathophysiological processes associated with MFS cardiovascular pathology. We then summarize the treatment options that have been developed based on this knowledge and are currently in different stages of preclinical or clinical development, provide a critical review of the limitations of current studies and highlight potential opportunities for future research.

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Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysms

Cited by 26 publications

References 48 publications

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

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