Before a new drug can be tested in humans, researchers must demonstrate that it has the potential to be efficacious and safe. An essential part of this process is to first test the drug in disease models – cells or animals that recreate some aspects of a human disease. A disease model can vary from a single cell to an animal like a mouse or a rat. In addition to testing drugs, these models can also be used to aid research about the biology of a disease.
ALS TDI: 25 Years of Setting the Standard for ALS Models
At the ALS Therapy Development Institute (ALS TDI), we employ a variety of different models to test potential ALS treatments and learn more about the disease. As the world’s most comprehensive preclinical drug discovery laboratory focused solely on ALS, we conduct all kinds of drug testing under one roof. In our lab, a drug may move from early testing in cells provided by participants in our ALS Research Collaborative Study (ARC), into smaller animal models like fish, and on to mouse models of the disease. Our clinical research, cell biology, and pharmacology teams work together closely to make sure that treatments that show potential can move from stage to stage – and model to model – as efficiently and effectively as possible.
Since soon after the organization’s founding 25 years ago, ALS TDI has been a leader in testing drugs in mouse models of ALS. At the time, effective animal models of ALS were relatively new tools for ALS researchers. Many animal models are created by genetically modifying them to demonstrate symptoms of a disease. However, introducing a human gene mutation into an animal does not necessarily mean that it will show symptoms of the disease – a necessity for testing if a drug is slowing or stopping those symptoms.
In the mid-90s, researchers discovered that mice genetically modified with a mutated human SOD1 gene would go on to develop motor neuron degeneration, muscle weakness, and paralysis like in human ALS. A mutation in this gene is responsible for one of the more common forms of familial ALS. This allowed researchers to observe whether potential drugs for the disease could slow or stop progression these symptoms in an animal model.
When ALS TDI began working with the SOD1 G93A mouse in the early 2000s, the ALS research community was still learning how to best use these models. At the time, the organization was relatively small and a new player in the ALS research space. However, the methods and best practices they established for testing drugs in SOD1 mice at that time have come to be recognized as the industry standard and are still used widely at many institutions conducting preclinical ALS research.
Expanding to Animal Models Beyond the SOD1 Mouse
While SOD1 G93A mice remain the most used animal model at ALS TDI and across the ALS space, we now have many additional tools to model the disease. These include other genetically modified animals like zebrafish as well as mice with other ALS-related mutations. Animal models currently in use for drug testing at ALS TDI include:
Of these mouse models, SOD1 mice display the fastest and most aggressive disease progression. This is a major reason they have remained the most common animal model of ALS for so long. The faster a model’s symptoms progress, the faster researchers can see whether a treatment is slowing or stopping them, reducing the timeframe for drug testing experiments.
However, because of the diversity of ALS in humans, developing additional models with different genetic characteristics remains a priority for ALS researchers. At ALS TDI, we also utilize mice with mutations in the Profilin 1 and TDP 43 genes. These models demonstrate increased lifespans and decreased symptom severity compared to the SOD1 mouse. Still, they remain useful to help provide additional insights into a treatment’s potential in different forms of ALS.
Zebrafish are small fish that are widely used in pharmaceutical research to model many diseases. At ALS TDI, we utilize zebrafish that have been modified with several versions of the C9orf72 mutation. Because of their small size and relatively rapid lifecycle, they represent a “happy medium” between cellular models of the disease and larger animals like mice. They can be used as an intermediary step between these cells and larger animals, allowing drugs to be tested in a model closer to the complex biology of a human, but in a relatively shorter timeframe. This can help to further weed out treatments that would likely fail before dedicating the several months that experiments in a mouse model usually take.
Additionally, these fish provide a chance to study the biology of the C9orf72 mutation — the most common form of familial ALS — in an animal model. Developing a mouse model with this mutation, along with other genetic or even sporadic forms of ALS, is also a high priority for ALS TDI researchers. However, thus far, mouse models modified with C9orf72 mutations do not develop symptoms of ALS, making them challenging models for drug testing.
Cellular Models at ALS TDI
In addition to our groundbreaking work with animal models, ALS TDI also maintains an industry-leading cell biology program. Nearly all cellular models of the disease currently in use at the institute have come from our ALS Research Collaborative (ARC) Study – the longest-running natural history study in ALS. Since 2014, people living with ALS participating in the study have been contributing biological samples, including cells that can be used to create models of the disease for study and drug testing.
To create a cellular model of ALS, it is helpful to look at the cells primarily affected by the disease – motor neurons in the brain and spinal cord. However, it is impossible to collect these cells from a living person. This presented a challenge for ALS researchers until the discovery of induced pluripotent stem cells (iPSC) in the mid-2000s. iPSCs are stem cells that can be reprogrammed from various kinds of cell in the body, and then “differentiated,” or coaxed to turn into any other kind of cell.
Using these techniques, ALS TDI researchers can take skin and blood cells donated by ARC participants and create motor neuron-like cells for use in our lab. Currently, the cell biology team has developed cell lines with this technique that model forms of familial ALS caused by SOD1, C9orf72, TDP43, and other mutations. Additionally, they have collected many cellular samples from people with sporadic ALS.
A major project in the near future will be to establish iPSC cell lines from these samples to characterize and create models of sporadic ALS. Researchers know very little about what causes or drives the disease in cases of sporadic ALS, despite the fact that it represents about 85% of cases of ALS. Because of this, it is currently impossible to create an animal model of sporadic ALS.
The Crucial Role of ARC Participants
Learning more about ALS in humans is key to developing better animal and cellular models of the disease. The ARC study is a crucial component of ALS TDI’s work to better understand the diverse biology of ALS. Through ARC, people all over the world contribute data about their disease progression, genetics, personal history, and more. These data fuel research at ALS TDI and are shared with others throughout the ALS space through the ARC Data Commons. Participation in the study is 100% remote, and anyone living with ALS or carrying an ALS-related genetic mutation anywhere in the world is eligible to sign up.
To learn more about how you can help contribute to ALS research by enrolling in ARC, click here.
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