Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company

Gromo, Gianni; Mann, Jessica; Fitzgerald, J. D.

doi:10.1101/cshperspect.a014092

Cited by 14 publications

(11 citation statements)

References 34 publications

(24 reference statements)

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“…A scientific case for MAP4K4 is suggested by many conventional criteria (“observational” biochemistry, mouse models, and rodent cardiomyocytes), although these, even taken together, are merely tentative or provisional indications of a functional role in humans. This standard pipeline for cardiac drug discovery—“flying blind” with respect to human efficacy—is notoriously failure prone (Fordyce et al., 2015, Gromo et al., 2014), prompting academic and industry-based investigators alike to embrace target validation in human cardiomyocytes from pluripotent stem cells as an accessible, scalable, transformative alternative (Bellin et al., 2012, Burridge et al., 2016, Cameron et al., 2013, Gintant et al., 2017, Lee et al., 2017b, Liang et al., 2013, Mathur et al., 2015, Matsa et al., 2014, Matsa et al., 2016, Sharma et al., 2017). Here, using hiPSC-CMs as the most relevant platform for gene silencing and drug discovery, we created small-molecule inhibitors of MAP4K4 through field-point modeling and screening in silico .…”

Section: Discussionmentioning

confidence: 99%

“…In 2018 alone, the US Food and Drug Administration approved 13 drugs for cancer, yet none for cardiac indications (US Food and Drug Administration, 2018). Among other recognized limitations, the conventional pipeline for cardiac drug development lacks any human preclinical model whatsoever for testing proposed counter-measures (Fordyce et al., 2015, Gromo et al., 2014). The routine cardiac platforms for predicting efficacy are inherently flawed, and the creation of novel approvable medicines is “dead” or “hibernating” (Fordyce et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

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MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

et al. 2019

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“…The preclinical development of new therapeutics or drugs involves multiple processes, such as drug screening, in vitro and in vivo pharmacological and pharmacokinetic activity assessments, and safety analysis ( Gromo et al, 2014 ). The discovery of hiPSCs provided a new platform that significantly changed preclinical drug screening and development ( Paik et al, 2020 ).…”

Section: Drug Development and Screeningmentioning

confidence: 99%

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering

Gähwiler

Motta

Martin

et al. 2021

Front. Cell Dev. Biol.

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Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications.

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“…Taken together, as timely assessment of these essential functional parameters of the heart is one of the critical steps in drug discovery [28,29], the zebrafish has the potential to fill in the gap between cellular expression systems or invertebrates and mammalian models facilitating the long run of CVD drug discovery [14,18,30,31].…”

Section: Aspects and Pitfalls During The Early Phase Of Cardiovasculamentioning

confidence: 99%

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Pott

Rottbauer

Just

2019

Expert Opinion on Drug Discovery

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Introduction: In the last decade, our armamentarium of cardiovascular drug therapy has expanded significantly. Using innovative functional genomics strategies such as genome editing by CRISPR/Cas9 as well as high-throughput assays to identify bioactive small chemical compounds has significantly facilitated elaboration of the underlying pathomechanism in various cardiovascular diseases. However, despite scientific progress approvals for cardiovascular drugs has stagnated significantly compared to other fields of drug discovery and therapy during the past years. Areas covered: In this review, the authors discuss the aspects and pitfalls during the early phase of cardiovascular drug discovery and describe the advantages of zebrafish as an in vivo organism to model human cardiovascular diseases (CVD) as well as an in vivo platform for high-throughput chemical compound screening. They also highlight the emerging, promising techniques of automated read-out systems during high-throughput screening (HTS) for the evaluation of important cardiac functional parameters in zebrafish with the potential to streamline CVD drug discovery. Expert opinion: The successful identification of novel drugs to treat CVD is a major challenge in modern biomedical and clinical research. In this context, the definition of the etiologic fundamentals of human cardiovascular diseases is the prerequisite for an efficient and straightforward drug discovery.

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Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company

Cited by 14 publications

References 34 publications

MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering

Streamlining drug discovery assays for cardiovascular disease using zebrafish

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