The RETHINK project

Forster, Roy; Bode, Gerd; Ellegaard, Lars; Laan, Jan Willem van der

doi:10.1016/j.vascn.2010.05.003

Cited by 56 publications

(11 citation statements)

References 10 publications

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“…12 With the increasing ethical concerns regarding the use of primates in non-clinical testing, attention has been increasingly focused on the potential use of minipigs as non-rodent alternatives for pharmaceutical testing. [13][14][15][16][17] As such, minipigs are becoming more frequently used for toxicological and PK studies of small molecules. [18][19][20] Recently, minipigs have been used to test the immunogenicity of therapeutic proteins; 21,22 however, limited data exist for the pharmacokinetics of macromolecules in minipigs.…”

Section: Resultsmentioning

confidence: 99%

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Zheng¹,

Tesar²,

Benincosa

et al. 2012

mAbs

124

110

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Section: Resultsmentioning

confidence: 99%

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Zheng¹,

Tesar²,

Benincosa

et al. 2012

mAbs

124

110

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“…With this in-mind, we have recently begun preliminary studies with our engineered HCEC grafts in mini pigs, which are fully compliant with anesthetic and postoperative experimental procedures following NIH regulations. These animals have become increasingly popular as preclinical disease models[80–82] and can serve as a valuable model for ocular conditions due to the similarity in corneal diameter, thickness, and refractive power to human corneas. We have established corneal endothelial dysfunction in mini pigs by scoring an area of corneal endothelium and then removing it from the anterior chamber (Fig.…”

Section: Transplantation Of Engineered Hcec Graftsmentioning

confidence: 99%

Engineering of Human Corneal Endothelial Grafts

Zhu

Tighe

Chen

et al. 2015

Curr Ophthalmol Rep

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Human corneal endothelial cells (HCEC) play a pivotal role in maintaining corneal transparency. Unlike in other species, HCEC are notorious for their limited proliferative capacity in vivo after diseases, injury, aging, and surgery. Persistent HCEC dysfunction leads to sight-threatening bullous keratopathy with either an insufficient cell density or retrocorneal membrane due to endothelial-mesenchymal transition (EMT). Presently, the only solution to restore vision in eyes inflicted with bullous keratopathy or retrocorneal membrane relies upon transplantation of a cadaver human donor cornea containing a healthy corneal endothelium. Due to a severe global shortage of donor corneas, in conjunction with an increasing trend toward endothelial keratoplasty, it is opportune to develop a tissue engineering strategy to produce HCEC grafts. Prior attempts of producing these grafts by unlocking the contact inhibition-mediated mitotic block using trypsin-EDTA and culturing of single HCEC in a bFGF-containing medium run the risk of losing the normal phenotype to EMT by activating canonical Wnt signaling and TGF-β signaling. Herein, we summarize our novel approach in engineering HCEC grafts based on selective activation of p120-Kaiso signaling that is coordinated with activation of Rho-ROCK-canonical BMP signaling to reprogram HCEC into neural crest progenitors. Successful commercialization of this engineering technology will not only fulfill the global unmet need but also encourage the scientific community to re-think how cell-cell junctions can be safely perturbed to uncover novel therapeutic potentials in other model systems.

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“…The most common animal species used to assess pre-clinical drug safety are rat as rodent species and beagle dogs and the Cynomolgus monkey ( Macaca fascicularis ) are accepted non-rodent models. In the last years the Göttingen minipig has gained growing attention as model for drug safety testing and translational medical research fueled by the RETHINK consortium [ 5 ]. These animals resemble many features of human anatomy, physiology, and biochemistry [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis and transcriptional output of the Göttingen minipig genome

et al. 2015

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BackgroundIn the past decade the Göttingen minipig has gained increasing recognition as animal model in pharmaceutical and safety research because it recapitulates many aspects of human physiology and metabolism. Genome-based comparison of drug targets together with quantitative tissue expression analysis allows rational prediction of pharmacology and cross-reactivity of human drugs in animal models thereby improving drug attrition which is an important challenge in the process of drug development.ResultsHere we present a new chromosome level based version of the Göttingen minipig genome together with a comparative transcriptional analysis of tissues with pharmaceutical relevance as basis for translational research. We relied on mapping and assembly of WGS (whole-genome-shotgun sequencing) derived reads to the reference genome of the Duroc pig and predict 19,228 human orthologous protein-coding genes. Genome-based prediction of the sequence of human drug targets enables the prediction of drug cross-reactivity based on conservation of binding sites. We further support the finding that the genome of Sus scrofa contains about ten-times less pseudogenized genes compared to other vertebrates. Among the functional human orthologs of these minipig pseudogenes we found HEPN1, a putative tumor suppressor gene. The genomes of Sus scrofa, the Tibetan boar, the African Bushpig, and the Warthog show sequence conservation of all inactivating HEPN1 mutations suggesting disruption before the evolutionary split of these pig species. We identify 133 Sus scrofa specific, conserved long non-coding RNAs (lncRNAs) in the minipig genome and show that these transcripts are highly conserved in the African pigs and the Tibetan boar suggesting functional significance. Using a new minipig specific microarray we show high conservation of gene expression signatures in 13 tissues with biomedical relevance between humans and adult minipigs. We underline this relationship for minipig and human liver where we could demonstrate similar expression levels for most phase I drug-metabolizing enzymes. Higher expression levels and metabolic activities were found for FMO1, AKR/CRs and for phase II drug metabolizing enzymes in minipig as compared to human. The variability of gene expression in equivalent human and minipig tissues is considerably higher in minipig organs, which is important for study design in case a human target belongs to this variable category in the minipig. The first analysis of gene expression in multiple tissues during development from young to adult shows that the majority of transcriptional programs are concluded four weeks after birth. This finding is in line with the advanced state of human postnatal organ development at comparative age categories and further supports the minipig as model for pediatric drug safety studies.ConclusionsGenome based assessment of sequence conservation combined with gene expression data in several tissues improves the translational value of the minipig for human drug development. The genome and gene ...

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The RETHINK project

Cited by 56 publications

References 10 publications

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Engineering of Human Corneal Endothelial Grafts

Functional analysis and transcriptional output of the Göttingen minipig genome

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