The mouse and human genomes are about 85% the same, and those similarities have made the mouse a useful tool for drug discovery. But mouse models have limitations. Certain mouse models don't always contain the hallmark signs of diseases that appear in humans, which is especially true for models of neurodegenerative disorders. And when it comes to cancer, countless drugs cure tumors in mice but don't work in humans.
Breeding and housing mice for research is also expensive, and animal research has become increasingly controversial. In an era of massive clinical trial failures and R&D cutbacks in Big Pharma, drug developers are searching for ways to test drug candidates more accurately and cost-efficiently before pouring millions of dollars into clinical trials.
Human pluripotent stem cells can help scientists understand cancer and cell regeneration, and genetics and genomics technology can now pinpoint genes associated with certain diseases and medical conditions, but what drug developers ultimately need to push a potential therapy toward FDA approval are reliable models for drug testing.
Neither animals nor two-dimensional cell culture assays are practical for predicting drug toxicity in human cells, particularly liver toxicity, but new technology like organs-on-chips and bioprinted tissues have the potential to test the safety of drugs more effectively for a myriad of diseases.
Below I've highlighted some organizations, from both the private sector and academia, that are working on alternative drug testing technology.
|Wyss Institute's lung-on-a-chip--Courtesy of Wyss Institute|
Leading the organs-on-chips revolution is Harvard University's Wyss Institute for Biologically Inspired Engineering. Wyss researchers have created microchips that mimic organ functions of the lung, heart, kidney and intestine using a technique that combines multiple types of cells from an organ on a microfluidic chip. Wyss scientists first reported their lung-on-a-chip in 2010 and are now working to build 10 different human organs-on-chips in total with plans of eventually linking them to replicate the physiology of a whole human body.
Just this month, Wyss scientists unveiled their newest tool for drug testing, dubbed bone marrow-on-a-chip, believed to be the first device of its kind that mimics the structure, functions and cellular makeup of bone marrow. Because of its complex nature, bone marrow has been difficult to replicate and as a result has only been studied intact in living animals.
Each individual organ-on-a-chip is about the size of a computer memory stick and is made of a clear, flexible polymer that contains hollow microfluidic channels lined by living human cells. The chips are designed to be translucent to allow researchers to observe how organs in the body work without actually seeing the real things at work.
The Wyss organs-on-chips have already captured the interest of Big Pharma and government institutions with their pioneering technology. Last year, AstraZeneca ($AZN) inked a partnership with the institute to use its technology in an effort to more accurately test drugs. AstraZeneca and Wyss scientists will use the technology to develop new animal versions of the chips, which will be used alongside human models to test the safety of investigational drugs.
In addition, the U.S. Defense Advanced Research Projects Agency (DARPA), NIH and the FDA are together investing nearly $150 million in research funding to speed development of the chips for use in testing the effects of chemical and radiation exposures on humans.
San Diego-based Organovo has developed a bioprinting method, called NovoGen Bioprinting, to create strips of liver tissue, about 20 cells thick, to use for experimental drug testing. The bioprinted tissue is made up of multiple cell types arranged in distinct spatial patterns that replicate features of natural tissue architecture. Specifically, Organovo is focusing on liver cells because of their wide use in the laboratory to evaluate the potential toxicity and efficacy of drugs.
In October the company achieved a key milestone with its fully cellular 3D printed liver, showing that the artificial tissue retained essential organlike functions for up to 40 days. The results are a good springboard for the company, which hopes to use the product candidate to assess toxicology issues in human liver cells over a long period of time. In contrast, 2D cell cultures have a performance period of about 48 hours.
|Liver tissue created with NovoGen Bioprinting--Courtesy of Organovo|
Tissue that remains responsive to drug testing for one month or longer would be a boon to pharma and biotech companies because it would mean that researchers could administer various doses of a drug on the same tissue over an extended period of time. That capability could result in more accurate toxicology data on drugs at an earlier stage of development.
Organovo said in April that it is making its 3D human liver tissue technology available to clients who have specific testing needs in their preclinical drug discovery programs. In the coming months, Organovo says it will provide fuller testing services.
University of Nottingham
Amir Ghaemmaghami and colleagues at the University of Nottingham have developed a simple 3D laboratory method to test asthma and allergy medications that mimics functions in the body.
With respiratory conditions like asthma and allergies on the rise, Ghaemmaghami and his team see a need for more effective drugs to treat these ailments, which are often associated with expensive hospital visits and absences from work and school.
Detailed in a study published in March in the American Chemical Society's journal Molecular Pharmaceutics, the team's new test would ideally replace animal testing and 2D testing, in which a drug is applied to a layer of human cells.
The test includes three types of human cells found in a person's airway epithelial cells, fibroblasts and dendritic cells. The cells were initially grown on individual scaffolds and then assembled into the 3D multicell tissue model. In the body, these cells appear close together and are involved in the development of respiratory conditions. When exposed to allergens and bacterial extract, the 3D model containing these cells reacted just like a real person's airway. The researchers say that the model has the potential to reduce the need for some animal testing of new drugs for respiratory conditions.
Another maker of microfluidic chips, New Brunswick, NJ-based HuREL also constructs advanced artificial tissues that evaluate the cellular responsiveness, metabolic competency and endurance of cells cultured in vitro, and that simulate pharmacokinetic interactions among multiple tissues and organs.
|HuREL's microfluidic biochip platform HuRELflow--Courtesy of HuREL|
HuREL's microfluidic biochip platform--dubbed HuRELflow--is made up of an arrangement of separate but fluidically interconnected "organ" or "tissue" compartments with each compartment containing a culture of living cells taken from or engineered to mimic the primary functions of the respective organ or tissue of a living animal.
In October, HuREL struck a deal with Sanofi ($SNY) to fulfill some of the drug giant's preclinical drug testing needs. The initial phase of the R&D collaboration will aim to validate HuREL's HuRELhuman 3D liver tissue coculture for use in toxicological studies as well as studies of drug metabolism and pharmacokinetics. Comprising a coculture of primary cryopreserved human hepatocytes, or liver cells, HuRELhuman in vitro liver tissue is designed to predict the effects of drugs on the human liver. Compared to other in vitro methods, HuRELhuman maintains its functionality over weeks instead of over the days or hours typical of most in vitro systems widely used by labs.
In future phases of the collaboration, Sanofi plans to use the company's HuRELflow microfluidic assay platform for use in drug testing.
|Solidus' MetaChip for mimicking metabolic reactions in the human liver--Courtesy of Solidus|
In 2005, researchers at the University of California, Berkeley, Rensselaer Polytechnic Institute in Troy, NY, and Solidus Biosciences produced a biochip, called a MetaChip--short for Metabolizing Enzyme Toxicology Assay chip--that mimics the metabolic reactions in the human liver. Their aim was to use the technology to conduct rapid screening of potential drugs and then identify those activated by the liver and throw out the toxic ones. Since then, Solidus has created and now offers several kinds of biochips, including the Data Analysis Toxicology Assay chip (DataChip), Metabolizing Enzyme Stability Assay chip (MesaChip), multiple enzyme chip (Multizyme Chip) and Transfected Enzyme and Metabolism Chip (TeamChip), for a variety of preclinical testing purposes.
The idea behind the technology is that while drug companies now have ways of rapidly generating new drug candidates, the existing preclinical testing methods have not kept pace. In other words, drug developers don't have a way to rapidly screen these candidates for toxicity.
Traditional toxicity screening involves cultured liver cells and even slivers of liver, but these methods often produce inconsistent results. The MetaChip contains cytochrome P450 enzymes--the liver's major detoxification enzymes--encapsulated in a gel that makes them immobile on a glass slide, so that many drug candidates can be tested simultaneously. P450 enzymes are responsible for the initial clearance of drugs from the body and the activation of prodrugs, those that are inactive or less than fully active when administered but are converted to an active form through a normal metabolic process.
-- Emily Mullin (email | Twitter)