Drug Discovery & Phenotyping

Support for Your Drug Discovery Project

We can provide support for your Drug Discovery project! hiPSC-CMs provide a novel platform for pre-clinical screening to detect a compound's potential to cause cardiotoxicity and pro-arrhythmia. In fact the FDA and other stakeholders in the drug discovery space are currently overhauling the guidelines for pre-clinical safety screening. This new initiative is called CiPA (Comprehensive in vitro Proarrhythmia Assay). The use of hiPSC-CMs is a central component of CiPA.

The Core laboratory and Dr. Jose Jalife (Director of the Center for Arrhythmia Research) are participants in the validation studies that aim to validate CiPA for pre-clinical compound screens. We have developed novel high throughput screens using mature hiPSC-CMs to screen for pro-arrhythmia and cardiotoxicity. Our platform is unique in its ability to detect Torsades de Pointes (TdP)-a life threatening cardiac arrhythmia that may be induced if a drug therapy negatively impacts ion channels of the heart. Other approaches measure surrogate markers for TdP, but we are able to detect this potential danger directly in vitro. Another unique platform enables the quantification of drug effects on contractile force development of 3D hiPSC-CM micro-tissues.

Contact Us

Email us today at cvcregenerationcore@gmail.com to perform pre-clinical screening of your compound for potential cardiotoxicity side effects. These assays will benefit your drug discovery project at any stage of the process, especially in the early phases!

You may also visit our Contact Us page for more information.

Key Platforms

Two key platforms/approaches are available for your Drug Discovery Project:

  1. CARTOX Well Plate Optical Mapping+2D monolayers

2. 3D hiPSC-CM micro-tissues for high content screening of drug effects on organogenesis and force generation.

We have developed novel 3D cell culture platforms to generate hiPSC-CM microtissues. These tissues are made by mixing hiPSC-CMs together with collagen and subsequently plating in each of these microwells (3x5 array). Now, a single 3D engineered heart tissue (EHT) can be made per well in 96 well plates for HTS. The 3D tissues can be imaged using CARTOX (left).

The CARTOX imager data output generates heat maps for important electrophysiology parameters including APD, triangulation, conduction velocity and calcium transient amplitude.

These examples show a beat frequency heat map (left) and a calcium transient amplitude heat map (right). Single well traces at the bottom show the superior signal to noise ratio and the high quality of gathered data.

  1. CARTOX in vitro optical mapping platform: Image 6 to 384 well plates and measure action potentials or calcium transients with high throughput processing.

Action potential recordings in multiple wells (6x6 array) of a 96 well plate. Voltage sensitive dyes (or calcium dyes) are used to detect compound effects on action potential duration and propagation. In this HTS a full 96 well plate can be imaged in 5 min to provide full dose response curves. Three compounds can be screened per plate. We are unique in that we can offer mature hiPSC-CM monolayers for your drug discovery project.

We generate monolayers of purified hiPSC-CMs to screen for cardiotoxicity and proarrhythmia. This is a control condition with normal rhythm. Optical mapping is employed to visualize electrical impulse propagation through the monolayer.

3D microtissues contract spontaneously and generate sufficient tension to bend microposts. We monitor micropost position to quantify force of contraction. Force measurement can be done simultaneously with calcium flux or action potential monitoring to provide comprehensive analysis of excitation contraction coupling. This is especially useful for development of new chemotherapy compounds which are notoriously culprits for causing cardiotoxicity.

Human TdP in a Dish! This monolayer of cells was generated using diseased human cardiomyocytes. The disease is caused by a mutation in a key contractile protein of the heart that is known to cause hypertrophic cardiomyopathy. This is abnormal propagation termed re-entry or also referred to as a rotor. This re-entrant activation pattern is the mechanism of TdP.