Advancing nonclinical innovation and safety in pharmaceutical testing

Baker, Elizabeth; Beck, Nancy A.; Berg, Ellen L.; Clayton-Jeter, Helene D.; Chandrasekera, P. Charukeshi; Curley, J. Lowry; Donzanti, Bruce A.; Ewart, Lorna; Gunther, Jane M.; Kenna, J. Gerry; LeCluyse, Edward L.; Liebman, Michael; Pugh, Catherine L.; Watkins, Paul B.; Sullivan, Kristie

doi:10.1016/j.drudis.2018.11.011

Cited by 11 publications

(8 citation statements)

References 9 publications

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“…The choice of culture system can, however, significantly impact cellular functionality and the expression of key phenotypic markers (Baker et al 2018;Lauschke et al 2016a, b;Lin and Khetani 2016). Culturing primary human hepatocytes as three-dimensional spheroids preserves many of the features which are rapidly lost in conventional 2D monolayers (Bell et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…new medicine to cause drug-induced liver injury (DILI) in man is, however, complicated by species differences in both the expression and activity of a number of proteins involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs (Martignoni et al 2006). In vitro systems which incorporate well-characterised human cells and/or tissue are therefore becoming increasingly important in the development of safe medicines (Baker et al 2018;Godoy et al 2013;Weaver and Valentin 2019).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity

et al. 2020

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In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatocytes (PHH) and non-parenchymal cells (NPC) and applied it to the investigation of acetaminophen-induced toxicity. Firstly, we titrated ratios of PHH:NPC and confirmed the presence of functional NPCs via both immunohistochemistry and activation with both LPS and TGF-β. Based on these data we selected a ratio of 2:1 PHH:NPC for further studies. We observed that spheroids supplemented with NPCs were protected against acetaminophen (APAP) toxicity as determined by ATP (up to threefold difference in EC 50 at day 14 compared to hepatocytes alone) and glutathione depletion, as well as miR-122 release. APAP metabolism was also altered in the presence of NPCs, with significantly lower levels of APAP-GSH detected. Expression of several CYP450 enzymes involved in the bioactivation of APAP was also lower in NPC-containing spheroids. Spheroids containing NPCs also expressed higher levels of miRNAs which have been implicated in APAP-induced hepatotoxicity, including miR-382 and miR-155 which have potential roles in liver regeneration and inflammation, respectively. These data indicate that the interaction between hepatocytes and NPCs can have significant metabolic and toxicological consequences important for the correct elucidation of hepatic safety mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity

et al. 2020

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“…In order to clarify the safety of ACE2-CS-PRT@PM in vivo, the acute toxicity of ACE2-CS-PRT@PM was evaluated in accordance with the guidelines for nonclinical safety evaluation of pharmaceutical excipients. 54 Thirty rats were randomized into 3 groups, and injected with normal saline and ACE2-CS-PRT@PM (at the dose of 1 and 2 mg/kg, respectively) via tail vein. After observation for 2 weeks, rats were sacrificed and the plasma was obtained to detect the levels of AST, ALT, CREA, and BUN by an automatic biochemical analyzer (Chemray 800, Shenzhen, China).…”

Section: Associated Contentmentioning

confidence: 99%

Biomimetic Nanoparticle-Mediated Target Delivery of Hypoxia-Responsive Plasmid of Angiotensin-Converting Enzyme 2 to Reverse Hypoxic Pulmonary Hypertension

et al. 2023

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Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vascular sustained constriction and progressive remodeling, which are initiated by hypoxia then with hypoxia-induced additive factors including pulmonary vascular endothelium injury, intrapulmonary angiotension system imbalance, and inflammation. Now HPH is still an intractable disease lacking effective treatments. Gene therapy has a massive potential for HPH but is hindered by a lack of efficient targeted delivery and hypoxia-responsive regulation systems for transgenes. Herein, we constructed the hypoxia-responsive plasmid of angiotensin-converting enzyme 2 (ACE2) with endothelial-specific promoter Tie2 and a hypoxia response element and next prepared its biomimetic nanoparticle delivery system, named ACE2-CS-PRT@PM, by encapsulating the plasmid of ACE2 with protamine and chondroitin sulfate as the core then coated it with a platelet membrane as a shell for targeting the injured pulmonary vascular endothelium. ACE2-CS-PRT@PM has a 194.3 nm diameter with a platelet membrane-coating core–shell structure and a negatively charged surface, and it exhibits higher delivery efficiency targeting to pulmonary vascular endothelium and hypoxia-responsive overexpression of ACE2 in endothelial cells in a hypoxia environment. In vitro, ACE2-CS-PRT@PM significantly inhibited the hypoxia-induced proliferation of pulmonary smooth muscle cells. In vivo, ACE2-CS-PRT@PM potently ameliorated the hemodynamic dysfunction and morphological abnormality and largely reversed HPH via inhibiting the hypoxic proliferation of pulmonary artery smooth muscle cells, reducing pulmonary vascular remodeling, restoring balance to the intrapulmonary angiotension system, and improving the inflammatory microenvironment without any detectable toxicity. Therefore, ACE2-CS-PRT@PM is promising for the targeted gene therapy of HPH.

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“…While the debate on the relevance and acceptability of animal experimentation remains polarized [1-4], animal experiments are still hard to avoid in the process of new drugs reaching the market. However, the predictive value of animal experiments has limits, and poor translation from animal experiments to humans may contribute to the high attrition rates in drug development [5].…”

Section: Introductionmentioning

confidence: 99%

“…While the debate on the relevance and acceptability of animal experimentation remains polarized [1][2][3][4], animal experiments are still hard to avoid in the process of new drugs reaching the market.…”

Section: Introductionmentioning

confidence: 99%

Predicting animal to human translation: A proof of concept study using qualitative comparative analysis

Leenaars

Teerenstra²,

Meijboom

et al. 2022

Preprint

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Drug development suffers from high attrition rates; promising drug candidates fail in clinical trials. Low animal-to-human translation may impact attrition. We previously summarised published translational success rates, which varied from 0% to 100%. Based on analyses of individual factors, we could not predict translational success. Several approaches exist to analyse effects of combinations of potential predictors on an outcome. In biomedical research, regression analysis (RGA) is common. However, with RGA it is challenging to analyse multiple interactions and specific configurations (≈ combinations) of variables, which could be highly relevant to translation. Qualitative comparative analysis (QCA) is an approach based on set theory and Boolean algebra. It was successfully used to identify specific configurations of factors predicting an outcome in other fields. We reanalysed the data from our preceding review with a QCA. This QCA resulted in the following formula for successful translation: ~Old*~Intervention*~Large*MultSpec*Quantitative Which means that within the analysed dataset, the combination of relative recency (~ means not; >1999), analyses at event or study level (not at intervention level), n<75, inclusion of more than one species and quantitative (instead of binary) analyses always resulted in successful translation (>85%). Other combinations of factors showed less consistent or negative results. An RGA on the same data did not identify any of the included variables as significant contributors. While these data were not collected with the QCA in mind, they illustrate that the approach is viable and relevant for this research field. The QCA seems a highly promising approach to furthering our knowledge on animal-to-human translation and decreasing attrition rates in drug development.

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Advancing nonclinical innovation and safety in pharmaceutical testing

Cited by 11 publications

References 9 publications

Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity

Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity

Biomimetic Nanoparticle-Mediated Target Delivery of Hypoxia-Responsive Plasmid of Angiotensin-Converting Enzyme 2 to Reverse Hypoxic Pulmonary Hypertension

Predicting animal to human translation: A proof of concept study using qualitative comparative analysis

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