Animal testing is a sensitive issue. Fifty years ago, we placed less value on animal life than we do today. Today, we therefore view the use of animals for laboratory research differently. As a foundation, we want to be transparent about how animal testing plays a role in PLN research. In this article we explain why it is currently necessary to use laboratory animals and what is being done to switch to alternatives.
In the Netherlands, it is permitted to use animals for research provided strict rules are met. First, an application must be submitted to the local animal experimentation committee. Here the research must meet the three v’s: replace, reduce and refine. Substitute means that an experiment can only be done in animals and no alternative exists. Reduce means that you accurately determine in advance how many animals you need and keep the number as low as possible.
Finally, by refine we mean that you take good care of the animals and reduce discomfort as much as possible. The application also sets strict requirements for the welfare and proper care of the animals. Obviously, the animals will receive proper nutrition, housing, play opportunities and care. If there is unnecessary suffering, euthanasia is applied. Research is therefore conducted on an animal-by-animal basis: the research and care of laboratory animals is regulated as well as possible.
The need for animal testing To understand a disease
Why is research with animals necessary? Roughly speaking, there are two types of research done in biomedical sciences: research to understand how health and disease work and research into new treatments. Fifteen years ago, there was almost no alternative to animal research. Now we can reprogram human cells into stem cells. From these stem cells, we can then make all kinds of cells found in the human body.
The major disadvantage of these cells is that they are actually more like cells as found in an embryo than in an adult human being. So tricks are needed to make the cells more mature. Otherwise, for example, you might have heart cells from a PLN carrier, but see no problems at all because the cells are still at a pre-birth stage. Still, this development is a great advance: because we can do research with human cells, fewer animal experiments are needed. In addition, humans differ from mice, for example, so it is easier to compare human heart cells to a patient than animals to a human.
THE NEED FOR ANIMAL TESTING TO FIND A TREATMENT
For research on treatments, animal testing is even more important. When a drug is developed, it is usually tested first on cells, then in animals and finally rolled out in clinical trials in patients. There are three properties of a drug that are important to know before it is administered to patients. You want to know (1) that it is likely to work well; (2) that it has no dangerous or unpleasant side effects; (3) how the drug behaves in the body.
The last point involves questions such as: Is it properly absorbed into the blood? Where does the drug end up? Into what molecules is it converted or broken down? And how is it excreted? We call this pharmacodynamics. This information is also needed by the American and European agencies that review and authorize drugs.
For the action of a drug, we can use human cell models, and a lot of them do. For finding side effects and determining pharmacodynamics, laboratory animals are important because you would like to expose all organs to a new drug. After all, side effects can also occur in unexpected places.
In addition, the cooperation of blood, liver and kidneys determine pharmacodynamics. Thus, understanding pharmacodynamics requires all of these tissues. Pharmacodynamics is important because it largely determines the dosage, administration and use of drugs. Consequently, the strict safety requirements of the U.S. and European drug approval agencies (the FDA and the EMA) almost always require that animal studies have been conducted before a treatment may be studied in patients.
In effect, then, this is a question without a good answer: do we place more value on the safety of the first patients who are administered the drug or on the animals used in the study? As a foundation, we would find it irresponsible if drugs were simply administered to PLN patients without knowing exactly what the drug does, what the side effects are and what the pharmacodynamics are. But, alternatives do exist for some studies. So in PLN research, we make full use of them.
Alternatives to animal testing
What are the alternatives to animal testing? Already mentioned is the crucial discovery of cells reprogrammed into stem cells, a discovery that received the Nobel Prize in Medicine in 2007. In addition to making heart cells, we can now make small heart tissues in the laboratory, complete with connective tissue cells and blood vessel cells. We can also make these cells from specific patients who have PLN R14del, for example.
A next step is to combine different organs on a plastic device. In the future, this could be used to replace some of the research with laboratory animals. Another important step was taken several years ago: it turned out to be possible to keep pieces of heart tissue from a removed heart (i.e., the diseased heart of a PLN patient who receives a donor heart) in culture for a while and use it for research. This also offers great advantages: it is real human tissue with the real disease and all the complexity of the human organ.
The one disadvantage of this model is that the patient was already very sick. With treatment, we actually want to intervene much earlier, when someone is not so sick yet. Finally, computer models play an important role. Computer models can be used for understanding PLN, but also in drug development and investigating pharmacodynamics.
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ANIMAL TESTING WITHIN THE POLICY
The FDA and EMA also see these changes and are gradually giving them a place in their policies. Currently, for drugs of a known class (e.g., gene therapy whose “packaging” has been previously tested in animals or humans and thus the pharmacodynamics are already known), it is no longer necessary to conduct animal tests. It is then possible, for example, to use stem cell models to show that a drug really works and is likely to have few side effects, then use computer models to understand the pharmacodynamics and then go to the patient without the need for animal studies. With an ever-increasing amount of data that can be used in computer models and in research, this presents more opportunities.
OUR ROLE AS A FOUNDATION WITHIN THE USE OF LABORATORY ANIMALS
PLN Foundation is pushing hard to use these other models. In cooperation with universities, the Foundation has already had dozens (!) of stem cell lines made from carriers and family members and now even has its own mobile laboratory to facilitate this. Studies are underway in Utrecht, Maastricht, Enschede and Stanford using these stem cell lines in complex 3d models. Heart tissue from PLN patients is also being cultured at several sites for research. This is still a relatively new technique but is very promising. And finally, we have funded a project in which drugs are screened based on computer analysis.
This involved looking at what goes wrong in PLN and what drug could counteract these effects. We are currently researching one of the candidates that came out of this. In addition, we want to use an important new computer model in future research. This program makes predictions about drugs that could potentially bind to PLN. This model was awarded the Nobel Prize in 2024. However, laboratory animals are also badly needed for much PLN research. Developing a (gene) therapy without laboratory animals is unfortunately not possible. Animal welfare is a high priority for us, but we also recognize reality: without laboratory animals, there is not going to be a new safe treatment for PLN R14del.