In Vitro Using Human Cells and Cultures
In vitro toxicity testing is the scientific analysis of the effects of toxic chemical substances on cultured bacteria or mammalian cells. In vitro (literally 'in glass') testing methods are employed primarily to identify potentially hazardous chemicals and/or to confirm the lack of certain toxic properties in the early stages of the development of potentially useful new substances such as therapeutic drugs, agricultural chemicals and food additives.
Modern in vitro toxicity testing methods can be more useful, more time and cost-effective than traditional test methods.
Examples of Companies Developing/Using In Vitro Methods
AxoSim’s mission is to leverage their 3D “nerve-on-a-chip” technology to accelerate the development of safer, more effective therapies. AxoSim's diverse team of scientists, engineers, and entrepreneurs are committed to tackling critical problems in pharmaceutical research. AxoSim’s advanced assays enable the biomimetic organization of neurological tissue in vitro to facilitate the high content screening of drugs that is both faster than animal testing and more predictive than current cell-based models. These clinically-relevant, benchtop models can help shorten preclinical development time and reduce the costs of bringing novel pharmaceuticals to market. http://axosim.com/
Pioneering contract research laboratory CeeTox uses human cell-based in vitro (test tube) toxicity screening to test drugs, chemicals, cosmetics, and consumer products. CeeTox scientists have many years of experience in pharmaceutical drug discovery. This knowledge has been used to develop and validate in vitro screening models for assessing toxicity. The Acute Toxicity Screen cell-based system accurately identifies compounds that would produce acute toxicity in a rat 14-day repeat-dose study. Learn more.
Founded in 2010, Empiriko’s business model was inspired by decades of experience working in the healthcare and life sciences industry. They have observed firsthand the challenges faced by scientists, clinicians and decision-makers responsible for taking drugs from concept to commercialization. Empiriko’s Biomimiks™ technology has been designed to meet industry challenges directly – enabling researchers and clinicians to work more iteratively and rapidly, gain the comprehensive information they need to develop better and safer compounds, optimize clinical trial design and treat patients more effectively. http://www.empiriko.com/biomimiks/technology
Hurel provides a technological substitute for animal testing, and an experimental platform for generating in vitro cell-based data of superior predictive relevance to the human organism.
Animal testing can be slow, and many researchers question how well an animal's response to a chemical predicts human reactions. By eliminating the time, money and potential inaccuracies associated with animal testing, Chief Executive Robert Freedman estimates Hurel's test could shave $100 million off the roughly $1 billion cost of developing a new drug. Technology Aims to Replace Animal Testing 2010 US News, Science. Learn more.
Founded in 2009, InSphero AG has become the leading supplier of organotypic, biological in vitro 3D microtissues for highly predictive drug testing. The Swiss start-up counts all of the top 15 global pharmaceutical, the number 1 cosmetics and 3 of the top 10 chemical companies as customers. InSphero enables customers to develop novel drugs and substances faster, more efficiently and safer. By testing these compounds in the lab using InSphero's unique and patented 3D InSight™ Microtissues, our customers can identify promising drugs and toxic liabilities much more predictively at early development stages. This allows for better decision-making and saves both development cost and time to market.
InSphero's 3D InSight™ Liver Microtissues have shown to have organotypic cell composition and morphology, have a longer life time and be more accurate in predicting compound efficacy and drug-induced toxicity by customers around the world. Recent additions to the product portfolio include pancreatic islet microtissues for diabetes and toxicology research. Significant research results in the field using InSphero's microtissues continue to be published in peer-reviewed literature, and validated within the world's largest pharmaceutical companies and government institutions. Amongst InSphero’s collaborations are the EU Body on a Chip, Eurostars HTS-DILI, and HeCaTos projects, as well as a groundbreaking cancer screening initiative with the NIH's National Center for Advancing Translational Sciences (NCATS). http://www.insphero.com/
Institute for In Vitro Sciences
The Institute for In Vitro Sciences, Inc. is a non-profit research and testing laboratory dedicated to the advancement of in vitro methods worldwide. Founded in 1997, IIVS has worked with industry and government agencies to implement in vitro testing strategies that limit animal use while supplying key information for product safety and efficacy decisions. http://www.iivs.org/
In Vitro ADMET Laboratories (IVAL)
Based in Columbia, Maryland, IVAL seeks to enhance drug development efficiency through state-of-the-art contract research services. Their dedicated group of professionals have worked and collaborated with various government agencies and for small to big pharma both domestic and international. IVAL aims to expedite the drug development process by providing innovative research techniques to get data to decision-makers fast. By partnering with clients, IVAL serves as an extension of their research arm to get tomorrow’s solutions here today. http://www.invitroadmet.com/index.html
InvitroCue provides innovative products and services in the fields of in vitro DMPK, in vitro itoxicology and digital pathology utilizing cell-based models and image analytics. InvitroCue’s technologies have been developed and validated together with leading pharmaceutical companies and scientific collaborators, such as the Agency for Science, Technology and Research (A*STAR), National University of Singapore, Massachusetts Institute of Technology and renowned pathologists. The company uses these technologies and assays to support better decision making in preclinical studies, clinical trials and diagnostics. http://www.invitrocue.com
The Irritection Assay System predicts ocular and/or dermal irritation potential of cosmetics, consumer products, and pharmaceuticals. InVitro International is currently seeking validation at ECVAM. Learn more.
The company produces ready-to-use, normal (non-transformed), human cell-derived, fully differentiated, 3-D, organotypic in vitro TISSUE equivalents for use in product development/efficacy, claims substantiation, safety assessment, and target organ research applications. The EpiDerm™, 3D human cell based in vitro model, has been used successfully as an in vitro alternative in a number of toxicology tests, most notably Dermal Corrosion, Skin Irritation, and Dermal Phototoxicity. It has been validated by ECVAM. MatTek has other models including EpiOcular™, EpiAirway™, EpiVaginal™, and EpiOral™ (also EpiGingival™) Learn more.
Solidus' technology enables companies to adopt highly predictive in vitro toxicity screens that increase productivity and reduce compound attrition due to toxicity.
The DataChip/MetaChip technology is based on the combination of microscale biocatalysis (human P450-catalyzed metabolism of drug candidates), human cell culture (amenable for screening major cell types of the body), materials science (to all microscale fabrication and operation), and automation technology to achieve high throughput operation with bench top instruments.
The fundamentally distinctive advantages of the DataChip/MetaChip platform are the result of product and process characteristics designed and engineered to replicate the human metabolism process. Consequently, the platform features a 3D cellular environment that mimics that of human tissues in vivo. It has the ability to accommodate a diverse array of cells, metabolizing enzymes and enzyme mixtures, and a broad array of drug candidates. Combined with platform aspects that optimize cell growth, these system characteristics transform to robust competitive strengths of high throughput, high predictive reliability, low cost, and consistent reproducibility of toxicity profiles. Learn more.
Vaxdesign designs, develops, and manufactures in vitro models of the human immune system. Their mission is to prevent infectious disease by forecasting vaccine responses before clinical trials, and create a competitive advantage by providing predictive in vitro immunological models and assays. The MIMIC® System - is high-throughput, predicts a human response, and captures human diversity (using cells from donors selected for ethnicity, age, gender, prior exposure, and other factors). The MIMIC System has yet to obtain regulatory approval, yet reduces the use of animals. Learn more.
Human Body on a Chip
Emulate’s proprietary Organs-on-Chips platform achieves a new industry standard by predicting human responses to medicines, chemicals, and toxins more rapidly and with greater fidelity than animal models. The company’s mission is to commercialize its Organs-on-Chips bioemulation products, automated platform and software to enhance innovation and accelerate the development of pharmaceutical, chemical, cosmetic, and personalized medicine products. http://www.emulatebio.com/
Harvard Wyss Institute
Harvards Wyss Institute is working with pharmaceutical companies to design drug tests that use the organs on chips. These chips will allow researchers to observe the mechanism of both diseases and drugs. The researchers have already created a lung on a chip, an intestine on a chip, a kidney on chip, and bone marrow on a chip.1 The Institute is creating a 10-organ system. Dr. Ingber of the Wyss Institute predicts that these organs on a chip will be ready for regulatory use within 2-3 years. The goal is to link organs and tissues into an entire physical system. The Wyss Institute is developing partnerships and up scaling manufacturing to standardize procedures and models for large-scale use by pharmaceutical companies. This is part of the FDA/NIH/DARPA Microphysiological Systems Program. MIT is also working in collaboration with MatTek on creating a 10-organ human tissues system.
Learn more here and here.
NIH Microphysiological Systems Program
The NIH, US Food and Drug Administration (FDA) and the Defense Advanced Research Projects Agency (DARPA) partnered to accelerate the development of human microphysiological systems (MPS) that address challenges faced in predictive toxicity assessment and efficacy analysis of new molecular entities during the preclinical phase of drug development. Use of human MPS could provide better models for predicting the efficacy of new molecular entities in clinical trials Researchers anticipate improvements in predicting drug toxicities early in the drug development process through the use of MPS or human organs-on-a-chip will decrease the need to withdraw new therapies from the market and minimize or eliminate deaths due to unidentified drug toxicities. Sutherland et al. Stem Cell Research & Therapy 2013, 4(Suppl 1):I1http://stemcellres.com/content/4/S1/I1
Tissue Chip for Drug Screening Initiative
Tissue Chip for Drug Screening Initiative is a collaboration between NIH’s National Center for Advancing Translational Sciences (NCATS), the Defense Advanced Research Projects Agency (DARPA), and the Food and Drug Administration (FDA). This initiative was developed to streamline the drug development pipeline by improving the process of predicting whether drugs will be safe in humans. The Tissue Chip for Drug Screening initiative was designed to improve ways of predicting drug safety and effectiveness.
This initiative aims to develop 3-D human tissue chips that model the structure and function of human organs, and then combine them into an integrated system that can mimic functions of the human body. Once developed and integrated, researchers will use these models to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more cost-effective way than current methods. http://www.ncats.nih.gov/research/reengineering/tissue-chip/tissue-chip.html
Stem Cell Research
Induced pluripotent stem cells have the potential to transform drug discovery by providing physiologically relevant cells for toxic compound identification, target validation, compound screening, and tool discovery. The technology for generating IPS cells is advancing rapidly, as is the repertoire of cell types that can be differentiated.
Tissue-specific cells derived from IPS cells are currently being evaluated by the pharmaceutical industry for their utility in identifying cardiotoxic and hepatotoxic compounds as therapeutically relevant systems for modeling cardiovascular diseases, neurodegenerative disorders and metabolic disorders, as well as for generating patient-specific cell types.
Stem cells often provide a better substitute to study various cancers, liver and cardiac toxicity than traditional test methods.
Examples of Companies Developing/Using Stem Cell Technology
VistaGen - VistaGens versatile human pluripotent stem cell (hPSC) technology platform, Human Clinical Trials in a Test Tube, has been developed to provide clinically relevant predictions of potential toxicity of promising new drug candidates long before they are ever tested in humans. Their hPSC-based bioassay systems more closely approximate human biology than conventional animal testing and other nonclinical techniques and technologies currently used in drug development. Learn more.
Stemina Biomarker Discovery - Stemina Biomarker Discovery offers devTOX, an all-human based assay developed to predict the potential toxic impact of drugs and other compounds on human embryo/fetal development. devTOX is the first all-human based screen for assessing the toxicity of drugs and chemical compounds on human development. Learn more.
3D Printed Organs
Miniature human organs made by 3D printing could create a "body on a chip" that enables better drug testing. This idea has become a new bioprinting project backed by $24 million from the U.S. Department of Defense.
The 2-inch "body on a chip" would represent a realistic testing ground for understanding how the human body might react to dangerous diseases, chemical warfare agents and new drugs intended to defend against biological or chemical attacks. Such technology could speed up drug development by replacing less-ideal animal testing or the simpler testing done on human cells in petri dishes — and perhaps save millions or even billions of dollars from being wasted on dead-end drug candidates that fail in human clinical trials."5 Learn more.
Organovo is a publicly-traded company San Diego company leading the way in bioprinting technology. Bioprinting is a unique, enabling tool that combines biology and engineering to fabricate 3D tissues containing key elements of native tissue, including cellular composition and spatial architecture. By constructing the tissues from tiny 3D multi-cellular building blocks, the resulting tissues have a tissue-like cellular density from the time of fabrication through the time of use in assays or other functional evaluations. Cells coming from research cell line, stem cells, cancer cells can be put into their 3-D printer and the printer then builds a living tissue structure. While liver samples for research are expected to be available by the end of 2014, Organovo is working to create a wide array of tissue samples including kidney, cancer, lung, muscle, blood vessels, bone, cardiac and nerve samples.
Organovo is preparing to sell strips of liver tissue to drug makers this year to be used to test toxicity of potential treatments. The impact of this technology on drug development and eventually tissue and organ transplants could be significant. In January, 2014, Organovo said it was collaborating with the US National Institute of Health to develop new tools to hasten the drug development timeline. Currently, drugs may take 10 years to make it to market. Using 3-D printed tissue will enable a drug researcher to test many samples from different human cell types very quickly, providing a more precise look at possible problems. Organovo plans to present data on test tissues for breast cancer and healthy kidneys by March, 2015. The data would lay the groundwork for tissue transplants, and eventually organ transplants, using 3-D printed cells. Organovo’s five- and ten-year goals are first to use a patient’s own cells to print tissue strips that can be used to patch failing organs, and finally to be able to create entire new organs. Ultimately, the technology may help reduce organ shortages and cut transplant rejects as patients receive new organs constructed from their own cells. Learn more.
Bioinformatics and In Silico Methods (Virtual Patients, Virtual Clinical Trials, Virtual Organs)
Computer models have successfully predicted negative side effects in hundreds of current drugs, based on the similarity between their chemical structures and those molecules known to cause side effects. As a result, computer models offer a possible new way for researchers to focus their efforts on developing the compounds that will be safest for patients, while potentially saving billions of dollars each year that goes into studying and developing drugs that fail.6
According to PriceWaterhouseCoopers, virtual R&D advances will reshape the current R&D model by 2020. “With the advent of virtual patients, it will be possible to “screen” candidates in a digital representation of the human body which can be adjusted to reflect common genetic variations and disease traits, such as a weakened cardiovascular system. This will show whether a molecule interacts with any unwanted targets and produces any side effects, and in what circumstances it does so. Predictive analysis will then enable researchers to assess how the molecule is likely to be absorbed, distributed, metabolized and excreted; what long-term side effects it might have; what free plasma concentration is needed to provide the optimal balance between efficacy and safety; and what formulation and dosing levels might work best.”7
Examples of Companies Developing/Using Bioinformatics
Entelos – Entelos is an in silico modeling and simulation software and services company delivering predictive technologies reducing risk, time, and cost of product development for pharmaceutical, biotechnology, nutrition and consumer products customers. The Company’s PhysioLab systems biology platforms generate virtual patient populations providing highly predictive analyses to develop safer and more effective drugs, foods and consumer products. Entelos’ understanding of patient variability has significant application to the emerging field of personalized medicine.
“Drug companies spend billions of dollars annually sponsoring trials that test drug safety and efficacy in humans,” said Shawn O’Connor, president and CEO of Entelos. “Despite this, fewer than 10% of drugs make it from Phase I to launch. Mechanistic modeling is revolutionizing the time and resources required to understand the effects of new drugs, and is simultaneously reducing the risk to humans who participate in clinical studies. Entelos PhysioLab platforms have been providing accurate predictions that have been relied on by world-class collaborators and clients for over 15 years. Their platforms define mechanisms of action and identify biomarkers for patient response – streamlining or eliminating the need for trial and error clinical studies – resulting in sizable cost savings, and time-to-market efficiencies.” Learn more.