Genetic Engineering & Biotechnology News

APR15 2017

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10 | APRIL 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News pany will also pursue other useful mechanis- tic assays for preclinical drug discovery. The CiPA Initiative Ventricular tachycardia due to torsades de pointes (TdP) has long been characterized and attributed to long QT intervals measured via electrocardiography. This phenomenon has been linked to the blockade of a potassium ion channel, a subunit of which is coded by the human ether-a-go-go-related gene (hERG). Normally, this channel, called the rapidly activating delayed rectifier potassium chan- nel (I Kr ), conducts a potassium current that plays a prominent role in defining repolariza- tion of the ventricular action potential. So, it should occasion little surprise that many developing drugs have been taken off the drawing board simply because in vitro stud- ies indicated that they had an ability to block the hERG channel. However, not all drugs that block the hERG channel cause TdP, and an increase in the QT interval would not necessarily cause TdP, either. This is the basis of the Comprehensive in vitro Proarrhythmia As- say (CiPA) Initiative. Gary Gintant, Ph.D., senior research fellow at the department of integrative pharmacology and integrated science and technology at Abbvie, explains why it took so long to shift the focus off the hERG channel block and long QT syn- drome being the gold standard for the diag- nosis of TpD. "Many factors slowed this shift," Dr. Gintant explains. These include (a) "a gen- eralized acceptance of the present approach by most (despite the possibility of removing drugs from drug development due to false- positive findings leading to discontinuation of novel compounds)" and (b) "changing the culture and structure built around hERG/QT testing. A true paradigm shift was achieved, he but it required the efforts of an enthusi- astic group of followers (mostly volunteers) to raise awareness as well as generate data to convince tough-minded scientists. Such a group took time to build." The CiPA Initiative consists of three ele- ments: 1) the assessment of drug effects on human ventricular ion channel currents, 2) in silico integration of these ion channel ef- fects determining net effect on cardiac active potential, and 3) checking for discrepancies in fully integrated biological systems via stem cell-derived cardiac myocytes and hu- man ECG. Twenty-eight compounds have been se- lected for the study—12 for CiPA training/ calibration, and 16 for validation. Before the compounds were included in the study, each of them was categorized according to its risk (high, intermediate, or low) of causing TdP. The In Silico Working Group (ISWG) de- veloped a computer model of the adult ven- tricular myocyte, which the CiPA Initiative uses to predict clinical risk of drug-induced TdP. Human cardiac stem cell derived cardio- myocytes (hSC-CMs) are then used to con- firm the in silico results within the CiPA para- digm by assessing changes in the extracellular field potentials of spontaneously active hSC- CMs. This combination of both in silico and in vivo branches aims to diminish any doubts about the torsadogenic effects of drugs that have a positive benefit-to-risk ratio. Animal Models A huge challenge in predicting drug effi- cacy and toxicity is progressing from in vitro tests to animal models. Fortunately, animal models have shown continuous improve- ment. Contributing to this improvement is Taconic Biosciences, a provider of research models where Michael Seiler, Ph.D., works as a portfolio director. He focuses on com- mercializing genetically engineered models, such as Taconic's rasH2 mouse model. "The amazing thing about the rasH2 model, is that it cuts down the study time from two years to 26 weeks," asserts Dr. Seiler. He adds that it not only saves time and money, but also allows for more accu- racy by preventing spontaneous tumors and false positives. This rapid tumorigenic response, which is Drug Toxicity Continued from page 9 Drug Discovery b i o l o g i c s @ e u r o g e n t e c . c o m | T E L . : + 3 2 4 3 6 6 6 1 1 6 | F A X : + 3 2 4 3 6 5 1 6 0 4 www.eurogentec.com Scalable from 1g to kg under GMP When it's scalable GMP plasmid manufacturing, it's Eurogentec. c Super-coiled and linear GMP plasmid platform c Scalable from 1g to kg under GMP c For human clinical and commercial use c cGMP manufacturing since 1994 Eurogentec is a full service CDMO specialized in the production of plasmid DNA for use in human clinical trial or as critical raw materials for viral vector production. TACO N I C .CO M | 1 ( 8 8 8 ) 8 2 2 - 6 6 4 2 D OW N LOA D TACO N I C ' S W H I T E PA P E R A B O U T R AS H 2 A N D C A R C I N O G E N I C I T Y T E ST I N G AT TACO N I C .CO M / R AS H 2 -W H I T E PA P E R 75% Faster and More Accurate Carcinogenicity Testing PA1053-EN-1703 The Role of rasH2 in an Evolving Pharmaceutical Carcinogenicity Landscape Taconic Bioscience's rasH2 mice enable you to perform short-term carcinogenicity testing of compounds on a much faster time line— reducing the in-life portion of your study to 1 /4 of a traditional two year study. The use of rasH2 is approved by the FDA and the International Conference on Harmonisation (ICH) S1B Guideline 1.

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