ALS Natural History: How to Turn Real-World Experience into Real Progress in ALS Research
- EverythingALS Editorial
- May 13
- 5 min read
Updated: May 15
Introduction
On April 16, 2025, EverythingALS hosted a deeply informative Expert Talk titled “ALS Natural History: How to Turn Real-World Experience into Real Progress in ALS Research.” The session featured Dr. David Walk, Professor and Head of the Neuromuscular Division at the University of Minnesota. Dr. Walk addressed a wide range of audience-submitted questions spanning genetics, clinical trials, disease modeling, and international collaboration. This conversation shed light on how long-term, real-world patient data—known as natural history studies—can accelerate ALS research and drive more targeted, impactful treatment options for patients worldwide.
Featured Questions
I’m an ATN X2 gene carrier. How can I find more information about this? What are the other genes being worked on for ALS Research?
There’s a study about intervening taxin-2, which is a complicated gene, and its impact on ALS is a little different than many other genes. The clinical trials, both observational and interventional, are listed on clinicaltrials.gov. EverythingALS also lists the major clinical trials. More research is being done with taxin-2 with respect to the genetic component.
What is a disease model, and how would the model inform treatment paths?
Modelling the progression of ALS has particular utility in terms of biostatistics and clinical trial design. Whether that’s designing a large trial and maximizing the likelihood of showing a benefit, or designing a futility study in a pragmatic trial focusing on a specific compound with minimal investments without integrating placebo, these models provide critical guidance to streamline this kind of research. For instance, around 200 people can be modelled with a specific drug without giving a placebo. Modelling can be done in advance by analyzing the difference between the outcomes anticipated versus the outcomes visible and concluding if the specific drug should be pursued further or not.
What if the disease has no connection with specific known genes? How can participating in a natural study help that?
This is not about a genetics study. This is about ALS and everything defined as ALS, that includes people at genetic risk. Although we've worked with all ALS, to be sure we are not doubling up and we are using the resources appropriately, our inclusion criteria include PLS, people at genetic risk for ALS, Kennedy's disease, and other motor neuron disorders. Although, Kennedy’s disease is genetic, and we believe that most of ALS is not mono-genetic. Studies have only begun to divulge the role of genetic susceptibilities for any disease.
Is it possible that a natural history dataset might be more likely to address specific set of questions, for example, why there is a higher rate of ALS occurrence in the state of Michigan?
I think we are less good at that than other epidemiological surveys, like what the CDC is doing. There’s someone Michigan who can speak to that much better than I, that is Steve Goutman. But we have the disadvantage of being specific to individual clinics.
How many patients are there in the database now, and how large would you like the ALS research database to grow?
We do have data on approximately 3,000 individuals going on for around 10-11 years. I believe there are around 1,100 who are presently contributing data to the dataset. We are adding a few sites each year and it’s a little bit complex, because what I am leading is fortunate to have received is FDA funding and there are some sites that have been brought on that are not part of the FDA project. We are adding a couple of them per year and as long as we have the money to fund those sites, we are bringing them on to get the best numbers we can.
Is it possible to get any trial drugs outside the US, specifically Turkey? Are there any updates on international collaborations and given all the changes in the world?
I know very little about access in Turkey or in much of the rest of the world. I will say that I have not seen a change in the collaborative spirit of clinicians and scientists and there are some barriers, but let’s hope that we can continue to move forward.
Is there any more information on expanded use of treatments such as Tofersen?
Tofersen is only being used in individuals with SOD-1 variants, although there are certain variants with some controversy about pathogenicity. There may be a role of SOD-1 in certain other individuals or more broadly in ALS, but I’m not sure how compelling the information is.
The real-world evidence with Qalsody for people who have SOD-1 mutations is continuing to be remarkably good. So, there’s people whose diseases are stabilizing and really doing quite well. There are rare cases of inflammatory and autoimmune reactions like idiosyncratic causes. Some people also get infected with aseptic meningitis or myelitis, which is an inflammation of the spinal cord. These are very serious conditions and treatable with steroids. There are some recent studies to navigate the severity and the treatment process with steroids. But, the experience with Qalsody as a treatment for SOD1 is, so far, better than the expectations of the people from the clinical trial data.
Further, it is extremely important that people undergo genetic testing at the time of diagnosis as there are emerging or experimental antisense nucleotides or other rare ALS genetic forms. And, it’s a directly targeted backdoor to potentially effective therapy for those individuals. The objective is to not let anyone miss out on being a candidate for antisense therapy, whether it’s the one approved by FDA, or others that might come along.
What can be done for folks who have been diagnosed with ALS for years? What needs to be tested? How should the folks who have been diagnosed with ALS for years navigate through?
Expanded Access Programs, or EAPs, are a good example because some individuals with ALS will benefit in EAPs. There are ways to impact somebody’s care, regardless of the duration of the disease. And, one of the things that might be challenging, as a clinician, is knowing somebody over a period of 5 – 10 years or more in the clinic, it’s easy to get fooled and think that things are not moving much, but as a matter of fact they are. And, if the clinician is not looking at their, examination, symptoms, or the scores, he or she can miss subtle changes. Even treatments that offer modest or slow benefits can be meaningful. For instance, if someone has been living with the disease for 5 to 10 years, and a therapy can help them walk for an additional 2 years instead of just 6 months, that’s a significant impact.
In other diseases like HIV or traumatic brain injury, researchers learned a lot by studying people who progressed slowly, like those who had HIV for a decade but never developed AIDS, or boxers who were punched in the head for years and never developed traumatic brain injury. The objective was to understand what was different about them. The probable answer lies in efforts like natural history studies, which collect clinical information systematically. With reference to gene testing, some studies suggest that a specific gene might be protective and more common in people with slowly progressing ALS who have a particular mutation. This redirects the focus towards new therapeutic targets. The only way to uncover this is by collecting data from people with slow and long-progressing ALS in a rigorous and coordinated way. For example, generating neurons from people with PLS and people with ALS, and specifically making spinal motor neurons to see if they have some kind of protective factors that people with ALS should have.
Conclusion
Dr. Walk’s insights emphasized the critical role of collaborative ALS research, genetic testing, and patient participation in shaping the future of ALS care. From exploring gene-based therapies like Tofersen to understanding slow disease progression in long-term patients, the conversation reinforced that every patient’s data matters. Continued global participation in natural history studies and clinical trials not only informs current treatments but opens new possibilities for the ALS community. As research advances, so does the hope for more effective, personalized care and ultimately, a cure.
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