Animal testing is a crucial part of developing new medicines, but it is accompanied by a host of ethical concerns. Stem cell models could eventually make it unnecessary.

Nowadays you can order a rat with Parkinson’s Disease or a naturally diabetic dog as you would any product on internet, but the ethical issues surrounding animal testing beg the question, are there equally relevant models that don’t come with the moral dilemma? There are indeed alternatives, but they may not be obvious.

Stem cells could be one of the alternatives, according to the European Commission’s Joint Research Center on alternative methods to animal experimentation in research and regulation. While attention to stem cells has been focused on potential in regenerative medicine, they have also earned a reputation in R&D for their capacity to produce human tissues and to model diseases. Indeed, they could lead to the development of more ethical, efficient and economical tools that could fast track R&D.

I believe the biggest impact to date of iPS cell technology is not regenerative medicine, but in making disease models, drug discovery, and toxicology testing […] Those somatic cells are very useful to recapitulate disease models based on the patient’s phenotype and to perform drug screening.” S. YamanakaNobel Prize winner for Stem Cell Research

Emerging solutions: stem cell models of disease

Emerging solutions: stem cell models of disease

Current cancer studies count on tumor cells isolated from patients, and those of genetic diseases can be facilitated by patient-derived immortalized cell lines. But these cell models leave much room for improvement: disease phenotypes are often specific to cell types that are difficult to isolate and cannot be continuously grown.

Human pluripotent stem cells (hPSCs) could be the best alternate disease model yet. These normal primary cell lines have an intrinsic capability for indefinite self-renewal, which gives them the potential to adopt any cellular fate through differentiation. And they’re available in a wide variety! In June 2016, no less than 369 human embryonic stem cell lines were eligible for use in research funded by the National Institutes of Health.

Some CROs like Cytoo are also already offering solutions like iPS-derived cardiomyocytes that can be organized and connected to reconstitute cardiac fibers; 3D spheroid cellular models compatible with HCS; and myotube models from fully maturing human primary myoblasts.

With all these new possibilities, let’s look more closely at how stem cells can replace animal testing!

baishev

Toxicity Screening

Animal testing is usually associated with determining if a product is toxic, and a team at GE Healthcare is pioneering a stem cell model to avoid using live creatures. The company’s researchers are developing human cell-based assays in drug discovery and predictive toxicity, and in 2012, they published encouraging results from a toxicity screen of compounds in heart cells.

As predicted, the cells were damaged by known toxic compounds; researchers were also able to identify drugs with toxic effects that were only discovered after the drugs had reached the market. This result indicates that such screening would be a powerful tool to detect candidates that lead to harmful toxicity.

Accordingly, Genentech is already using ESC- and iPSCderived cardiomyocytes from GE Healthcare and Cellular Dynamics International (CDI), a FUJIFILM company to build a cruelty-free model testing toxicity and detecting side effects. Genentech’s high-throughput models assess cardiotoxicity for drugs in development and investigate the specific mechanisms of cardiotoxicity during preclinical in vivo studies or even in the clinic.

With this strategy, Genentech is establishing human cellular models that could not only replace animal models but outperform them altogether with better reproducibility and predictability.

Models of Diseases for High-Throughput Screening (HTS)

Less visible to the public but equally morally troubling are animals engineered to express a disease, but stem cells might have an answer to this dilemma as well. IPSC-derived disease models have been generated for monogenic diseases, including neurological disorders like Parkinson’s, as well as blood diseases, cardiac syndromes, diabetes and hepatic disorders. The first disease-specific iPSCs of pathology were described in 2010, after they were derived from patients with an autosomal-dominant hearth disorder.

These tissue models are now being scaled up to systems that approach entire organs. In 2013 a research team built a simple model of cerebral organoids from hiPSCs that resembled fetal brain structures. This success could be the prototype for an artificial brain! Imagine how such brain tissue could become a vehicle for neurological disorder pathologies — it would be a perfect model for developers.

_74404000_ipsc-derivedkeratinocytescolonies-3

Skin stem cells can be grown by turning back the clock of adult cells. From the lab of Dr Dusko Ilic, King’s College London

Most recently, in August 2016, researchers at the Johns Hopkins Kimmel Cancer Center described their cell model of medulloblastoma to ScienceDaily. Instead of mouse cells, this model was built from stem cells, and the results it generated are more accurate reflections of patients’ responses to the drugs than those from its murine counterpart.

Systems of gastrointestinal and metabolic tissues have also been developed from hESC’s to support gut microbiota. This model could help to study gastrointestinal environment and the efficacy/toxicity of potential drugs on the gut. The cutaneous field might also be a good area for these new tools, as skin grown in the laboratory could replace animals in drug and cosmetics testing.

Personalized medicine

Since it is now possible to screen hugely different genomes with iPSCs, these cells may help model pathologies particular to an individual. Research efforts are increasingly focused on the individual progression of disease and the screening of drugs to find a ‘personalized’ treatment; banks of stem cells from a wide variety of genetic backgrounds would allow tailor-made medicine, making them attractive to companies looking to get their feet in the door to personalised medicine.

In an example of the application of stem cells to personal therapies, a team at Johns Hopkins Kimmel Cancer Center used RNA sampled from tumors to identify a “signature” gene expression. These sequences could be compared to similar signatures in three large databases of cell lines with different disease phenotypes and matched to particular pathologies with known effective treatments.

kulouku

The researchers reasoned that because of the genetic similarity between cancers, an effective treatment for one type would make it effective for the other as well. This finding opened not only a new avenue of personalised cancer therapies but also new stem cell sources for diseases models.

The ALS Association, Harvard Stem Cell Institute (HSCI), and Massachusetts General Hospital Neurological Clinical Research Institute are now taking advantage of the new model as well. In April last year, they announced a collaboration with GSK on a clinical trial to evaluate an anti-epileptic drug in ALS patients; in parallel testing, brain cells differentiated from each patient’s stem cells will be used to see if they can predict which patients might best respond to the medicine. Results are surely coming soon!

What can we expect from future?

Even if we can already build a simple functional system from stem cells, this does not mean that we have achieved making a truly human system: there are still many challenges to address like those regarding the 3D size of the model, interactions between targeted cells and bordering tissues, and multi-organ relationships to name a few.

Most critically, stem cells are limited to showing one specific organ’s reaction to a substance, but these cells won’t show how the entire human body would respond. Stem cells can’t (yet) act as a substitute for assessing a drug’s impact on the entire body. Don’t believe the hype from articles touting that “Cloning research ‘could replace animal tests’” or “Human skin grown in lab ‘can replace animal testing’” — there is still a long way to go to completely replace animal testing with stem cell models in drug development pathways. But we’re getting closer!

angellodeco

Cardiac differentiation from stem cells seems to have made the most progress towards this end. Other fields have farther to go: stem cell-derived hepatocytes still express immature markers, pancreatic cells continue to face low-yield differentiation, and neuronal differentiation still has difficulties in generating and distinguishing among the numerous cell types.

Some pharma heavyweights are already competing to bring these models up to speed. Roche contracted CDI to supply iPSCs to bolster the identification of novel drug candidates in a deal worth up to €77MBristol-Myers mirrored the move by acquiring iPierian for €675M. As stem cells progress, they may soon recognize the value of stem cell models and help push them to become a new standard model to test toxicity and disease progression!


Images: Piyada Jaiaree, Baishev, KuLouKu, agellodeco / shutterstock.com

Previous post

Sanofi Jumps into the Biosimilars Market aiming for Asia

Next post

UPDATE: More Good News on a Cannabis Derivative for Epilepsy