New non-animal methods for predicting cardiotoxicity

Cardiotoxicity is defined as damage or dysfunction occurring in the heart as a result of exposure to a chemical substance.  Cardiotoxicity is one of the major reasons given when the development of a drug fails or a drug is withdrawn from the market.  With the cost of bringing a new drug to market averaging $2.6 billion USD, there are pressing ethical and economic reasons to find a faster, more accurate way to predict cardiotoxicity.

Developments announced in the last few weeks are encouraging.  UC Berkeley researchers led by Professor Kevin Healy published a study of their functional “heart-on-a-chip:” a 3-dimensional network of adult stem cell-derived heart muscle cells linked together on a microfluidic platform that reproduces blood flow.  The cells beat normally, and responded appropriately to the effects of four well-described heart drugs (isoproterenol, E-4031, verapamil and metoprolol).  According to Healy, “Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy.” (See the open-access paper here.)

In addition, NC3Rs recently awarded its 2014 3Rs prize to Oliver Britton, a PhD student who created an innovative computational model of cardiac electrophysiology. Because the model incorporates within-species variations in heart properties (which are usually averaged in more simplistic models), it has the potential to more accurately identify potentially toxic drug compounds – allowing them to be pulled from development before animal studies begin.  Quoted in the NC3Rs press release, Professor Ian Kimber said of the model: “Mr Britton’s paper really stood out to the panel because of (its) potential as a replacement for early-stage animal tests in drug safety studies, across a broad range of disciplines. The model has also been developed into a piece of user-friendly software, encouraging uptake and use by industry, which could have an important impact on the reduction of animals in research.”

Human-relevant alternative models such as these have the potential to reduce the cost, time, and numbers of animals expended in drug development, while increasing human safety.

Watch video of the beating UC Berkeley “heart-on-a-chip”:

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Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science

…SeqAPASS provides us with a fast, efficient screening tool. Using it, we can begin to extrapolate toxicity information from a few model organisms (like mice, rats, zebrafish, etc.) to thousands of other non-target species to evaluate potential chemical susceptibility.

SeqAPASS provides an example of how EPA Chemical Safety for Sustainability researchers are leading the effort to usher in a new generation of toxicology practices that aspire to reduce the number of animals used, decrease costs, and increase the efficiency of chemical toxicity testing. The 21st century chemical toxicity testing strategy incorporates these ideals and has given rise to adverse outcome pathway (AOP) development and rapid, high-throughput chemical screening programs such as EPA’s ToxCast program.

Read more on the EPA’s science blog: Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science.

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Pfizer and HemoShear partner to predict toxicity in early stages of drug discovery

Pfizer Inc. and HemoShear, a privately held biotechnology company, are collaborating to develop methods to predict drug-induced vascular injury (DIVI) – a complication that slows or stops the development of many promising new drug candidates.

As Hemoshear’s press release explains:

Drugs in development may cause DIVI, such as inflammation or vascular lesions, in animals during testing for drug safety and toxicity. When this occurs, significant program delays and additional costs are incurred to investigate and explain the underlying biology and determine whether the compound is safe to move forward to human testing, or to determine if another compound would be safer. In some cases, decisions are made to stop the program altogether in the absence of a clear understanding of the injury and whether an animal response translates to human response.

The collaboration will make use of Hemoshear’s computational models and “translational tissue systems” — species-specific multidimensional tissue structures that replicate circulation and other physiological dynamics. Using these tissue systems, Hemoshear is able to run comparative studies (human tissues versus other animal tissues) that show whether, and how, human and animal responses differ.

The Pfizer/HemoShear collaboration has the potential to prevent unnecessary additional animal testing, and to reduce the cost and time it takes to bring new medications to market.


Read more about HemoShear’s translational tissue systems here.

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Growing in vitro toxicity test market catches investor attention

Increased demand for non-animal chemical safety evaluations and for greater efficiency in testing has led to a burgeoning new market for in vitro and in silico methods, and financial investment research companies are beginning to take notice.

In January, a report by BCC Research estimated that the combined in vitro/in silico test market – valued at $4 BILLION (USD) in 2011 and $4.9 BILLION in 2012 – will reach $9.9 BILLION in 2017.  The report also discusses the potential for continued growth in the market; quoted in one news release, report author Robert Johnson noted, “Our research indicates that the current wave of in vitro adoption globally will take at least five to seven years, and it could be decades before animal testing is replaced entirely.”

In April, Markets and Markets projected a market of $17,227 MILLION by 2018 (though this report seems not to include in silico tests). According to this analysis, “Europe was the largest contributor to the global in vitro toxicology testing market in 2013. It will also be the fastest growing region till 2018. The European market is witnessing growth as a result of strong government directives to altogether stop animal testing and replace in vivo testing by in vitro methods. The Asian countries…are also expected to register double-digit growth from 2013 to 2018 due to the low costs offered by the developing nations to conduct studies.”

In October, an analysis by Persistence Market Research reinforced these broad patterns (note that dollar figures are not provided in the summary available to the public).  The report notes that the market drivers are slightly different for the pharmaceutical and cosmetics industries: in pharmaceuticals, there is a growing trend “towards detecting the toxicity during initial stages of production,” while for cosmetics “support from regulatory authorities for using in-vitro and in-silico methods for studying toxicity of a substance is driving the in-vitro toxicity testing market…”  Persistence Market Research is also tracking growth in industry use of microfluidics: the market is projected to increase from $1,531.2 MILLION (USD) in 2013, to $5,246.4 MILLION in 2019, with Asia experiencing the highest growth. Microfluidic devices (such as the organs-on-chips being developed by the Wyss Institute, and 3-dimensional cell “co-cultures” such as those produced by Hepregen and HuRel) are increasingly used by pharmaceutical companies in their drug development and safety screening process, and are used in other health and manufacturing industries, as well.

For the purposes of predicting human responses to chemicals, non-animal test methods are proving to be as good as or better than the animal tests they are intended to replace. In addition, in vitro methods exponentially reduce the cost and time involved in identifying and safety- testing potential new pharmaceutical compounds.  This is no small matter; a recent study by the Tufts Center for the Study of Drug Development reports that it costs $2.6 BILLION (USD) to bring a new drug to market. Government initiatives to profile tens of thousands of already-marketed household and industrial chemicals stand to gain from improved speed and cost effectiveness, as well, and are among the key market drivers identified by these reports – along with regulatory activities such as REACH, and increasing public concerns about the ethics of animal research.

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Supercomputers link proteins to drug side effects

Image from Lawrence Livermore National Laboratories: “LLNL researchers Monte LaBute (left) and Felice Lightstone (right) were part of a Lab team that recently published an article in PLOS ONE detailing the use of supercomputers to link proteins to drug side effects. Photo by Julie Russell/LLNL”

Supercomputers link proteins to drug side effects.

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