To find the many treatments needed to end ALS, ALS TDI evaluates new research projects based on four key criteria. This blog details that strategic framework and demonstrates how it is applied in practice to guide the organization's work.
The ultimate goal of the ALS Therapy Development Institute (ALS TDI) is to end ALS for everyone with the disease. Because ALS is extremely heterogeneous, it will likely take many different treatments to accomplish this. That’s why we’ve made it our mission to fill the preclinical and clinical pipeline with as many promising potential treatments as possible.
Our nonprofit biotech model allows us the unique freedom to consider projects purely based on their potential to benefit the ALS community—but we must also carefully evaluate each opportunity to ensure our efforts deliver the greatest impact.
“We know that, to address the needs of everybody with ALS, we're going to need more than one therapeutic approach,” says Dr. Fernando Vieira, the CEO and Chief Scientific Officer of the ALS Therapy Development Institute. “Still, there is a perfect targeted drug discovery project that one could imagine in the hypothetical.”
Dr. Vieira says that he considers four key questions when evaluating a new research opportunity, based on this idea of a hypothetical “perfect” project.
What is the potential impact of this project on people with ALS? An ideal ALS drug discovery project would result in treatments that halt disease progression completely or even reverse its effects. How many people would this project benefit? An ideal project would help everyone with ALS—people with both sporadic and familial ALS, fast progressors and slow progressors, limb-onset or bulbar onset, etc. Are other institutions already working on this project? An ideal project would address a line of scientific inquiry and therapeutic development currently not being pursued by others in the field. How much background knowledge do we have about this project? An ideal project would target biological mechanisms of ALS that we understand well, using a similarly well-understood therapeutic approach. The technology required to manufacture the drug and study its behavior in models of ALS would be readily available to us.
An ideal ALS drug discovery project would result in treatments that halt disease progression completely or even reverse its effects.
An ideal project would help everyone with ALS—people with both sporadic and familial ALS, fast progressors and slow progressors, limb-onset or bulbar onset, etc.
An ideal project would address a line of scientific inquiry and therapeutic development currently not being pursued by others in the field.
An ideal project would target biological mechanisms of ALS that we understand well, using a similarly well-understood therapeutic approach. The technology required to manufacture the drug and study its behavior in models of ALS would be readily available to us.
While it is unlikely that any research project could perfectly meet all these criteria, many strongly embody one or more—even if they are lacking in others. For example, some potential ALS treatments, as well as currently approved medications like edaravone and riluzole, may provide small benefits to large numbers of people with the disease. Others, including antisense oligonucleotides (ASO) like tofersen, provide potentially larger benefits, but only to people with certain genetic mutations that make up a small percentage of the ALS population.
At ALS TDI, the ideas behind these projects come both from our own internal research into the disease and suggestions from outside collaborators. In both cases, says Dr. Vieira, we apply the same framework to decide whether it is a project we will take on.
“The ideal project would stop or reverse the disease for all people with ALS,” he says. “We would know a lot about the biology, and no one else would be working on it. Of course, with our current understanding, that project does not exist. But, when we consider what projects we will dedicate our time and resources to, those are the four features we consider.”
To demonstrate how ALS TDI evaluates projects using these criteria, here are three examples from our current research portfolio:
In 2019, ALS TDI researchers discovered that a class of drug called type 1 PRMT inhibitors can alter ALS-linked proteins associated with the C9orf72 mutation. Recent studies indicate that related type 1 PRMT modulators may also treat other types of ALS. ALS TDI is advancing type 1 PRMT inhibitors into animal testing to assess their potential for human trials.
What is the potential impact of this project on people with ALS? While it is difficult to know how a drug will affect people with ALS before it reaches human clinical trials, research at ALS TDI has indicated these drugs are protective in cellular models of ALS. They have also shown promising results in animal testing. How many people would this project benefit? C9orf72-related ALS is the most common familial form of the disease, and mutations in the gene have also been found in a small percentage of cases of sporadic ALS. While we know more about these drugs’ potential to help people with C9orf72 mutations, some research has indicated they may also benefit people with other forms of ALS. Are other institutions already working on this project? While type 1 PRMT inhibitor drugs have been studied in other diseases, research in ALS has been extremely limited prior to this project at ALS TDI. How much background knowledge do we have about this project? Type 1 PRMT inhibitors affect an ALS drug target discovered by ALS TDI in 2019. While this is a relatively new idea for therapeutic intervention, our research has positioned us as leading experts in applying this approach to ALS.
While it is difficult to know how a drug will affect people with ALS before it reaches human clinical trials, research at ALS TDI has indicated these drugs are protective in cellular models of ALS. They have also shown promising results in animal testing.
C9orf72-related ALS is the most common familial form of the disease, and mutations in the gene have also been found in a small percentage of cases of sporadic ALS. While we know more about these drugs’ potential to help people with C9orf72 mutations, some research has indicated they may also benefit people with other forms of ALS.
While type 1 PRMT inhibitor drugs have been studied in other diseases, research in ALS has been extremely limited prior to this project at ALS TDI.
Type 1 PRMT inhibitors affect an ALS drug target discovered by ALS TDI in 2019. While this is a relatively new idea for therapeutic intervention, our research has positioned us as leading experts in applying this approach to ALS.
“When C9orf72 mutations emerged in 2011 as a common cause of familial ALS, it seemed to be important to prioritize that,” says Dr. Vieira. “We found that type 1 PRMT inhibitors were protective against cell death caused by C9 toxic dipeptides in our own lab. This gave us a foothold of knowledge in a relatively large subset of people with ALS, in an area where nobody else was working.”
mRNA represents a relatively new therapeutic modality, or type of drug, in all of biomedicine, particularly in central nervous system diseases like ALS. In partnership with researchers at the University of Pennsylvania, ALS TDI is advancing mRNA technology for ALS and other CNS diseases. Together, we’re developing lipid nanoparticles to deliver mRNA drugs to the brain and spinal cord.
What is the potential impact of this project on people with ALS? Unlike type 1 PRMT inhibitors, mRNA represents a new class of drugs in ALS. This therapeutic modality has the potential to precisely target certain genes and “turn them up,” or increase the expression of certain proteins. For people with cases of ALS that involve underexpression of particular genes, these treatments could be profoundly impactful. How many people would this project benefit? This could potentially benefit anyone with familial or sporadic ALS in which a target is underexpressed. Are other institutions already working on this project? ALS TDI and our collaborators are among the first to investigate mRNA therapies for ALS. How much background knowledge do we have about this project? mRNA medicines are relatively new, but their use in vaccines, particularly for COVID-19, has led to a great deal of advancement and improved understanding. However, because this may be the first investigation of its use in neurodegenerative diseases, we are working to learn more about its potential advantages and challenges.
Unlike type 1 PRMT inhibitors, mRNA represents a new class of drugs in ALS. This therapeutic modality has the potential to precisely target certain genes and “turn them up,” or increase the expression of certain proteins. For people with cases of ALS that involve underexpression of particular genes, these treatments could be profoundly impactful.
This could potentially benefit anyone with familial or sporadic ALS in which a target is underexpressed.
ALS TDI and our collaborators are among the first to investigate mRNA therapies for ALS.
mRNA medicines are relatively new, but their use in vaccines, particularly for COVID-19, has led to a great deal of advancement and improved understanding. However, because this may be the first investigation of its use in neurodegenerative diseases, we are working to learn more about its potential advantages and challenges.
“The potential of mRNA as a platform to help many people is very high,” says Dr. Vieira. “There are lots of different medicines you could imagine inventing that address drug targets such as TDP-43 functional insufficiency, not enough Stathmin-2, not enough FUS, or not enough NEK-1. There are many, many targets that could benefit if we figure this out.”
The ALS Research Collaborative (ARC) is an initiative to collect and share comprehensive data from people with ALS to learn more about the disease and accelerate the discovery of treatments. This ongoing natural history study has already led to the discovery of new prototype biomarkers in ALS and is vital to much of the research carried out at ALS TDI.
What is the potential impact of this project on people with ALS? This research project is further removed from direct therapeutic development. However, by learning more about the disease, we can enable the development of many different drugs, both in our own lab and throughout the ALS field. By discovering new biomarkers, we can speed up diagnosis and make clinical trials faster and more efficient. By researching risk factors, we can enable earlier detection and diagnosis, uncover preventative strategies, and develop more targeted treatments. How many people would this project benefit? The goal of this study is to learn more about ALS and power ALS research at ALS TDI and across the field. By helping to advance the global effort to end ALS, this research has the potential to benefit anyone with the disease. Are other institutions already working on this project? There are several natural history studies ongoing in ALS but ARC, which began in 2014, is the longest running. All data collected by the ARC study are also shared with the ALS research community through the ARC Data Commons. How much background knowledge do we have about this project? ALS remains a poorly understood disease. 85% of cases still have no known cause. A natural history study like ARC is important for generating the background knowledge that can power all other research projects.
This research project is further removed from direct therapeutic development. However, by learning more about the disease, we can enable the development of many different drugs, both in our own lab and throughout the ALS field. By discovering new biomarkers, we can speed up diagnosis and make clinical trials faster and more efficient. By researching risk factors, we can enable earlier detection and diagnosis, uncover preventative strategies, and develop more targeted treatments.
The goal of this study is to learn more about ALS and power ALS research at ALS TDI and across the field. By helping to advance the global effort to end ALS, this research has the potential to benefit anyone with the disease.
There are several natural history studies ongoing in ALS but ARC, which began in 2014, is the longest running. All data collected by the ARC study are also shared with the ALS research community through the ARC Data Commons.
ALS remains a poorly understood disease. 85% of cases still have no known cause. A natural history study like ARC is important for generating the background knowledge that can power all other research projects.
“ARC is an open-ended study that aims to collect all of the data needed to unlock this disease, over as much time as necessary,” says Dr. Vieira. “As a nonprofit biotech, we are uniquely positioned to pursue projects like this, because we don’t have investors looking for money to come back to them within a timeframe. Instead, we have stakeholders who are looking for cures as fast as possible. With the ARC Study, we can make ‘as fast as possible’ faster. Not just for us, but for everybody working to end ALS.”
As a lab dedicated to attacking ALS from multiple angles, ALS TDI is working relentlessly to advance new treatments and learn more about the disease. To learn more about ALS TDI and our active research programs, click here.
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