Neuromuscular Rehabilitation and Recovery of ALS Disease: An Update on Tofersen for SOD1 ALS and Broader Implications for ALS Treatment
- Hetvi Vashi
- Jun 12
- 10 min read
Updated: Jun 16
INTRODUCTION:
The advancements in ALS treatment particularly for genetic forms like SOD1 ALS have opened new avenues for disease stabilization and functional recovery. Tofersen, an antisense oligonucleotide therapy, is at the forefront of this transformation, showing promise in reducing neurofilament levels, slowing disease progression, and improving certain patient outcomes. Alongside pharmaceutical interventions, neuromuscular rehabilitation is emerging as a vital component of the care paradigm, potentially reshaping how we approach recovery in ALS. Through expert insights from leading clinicians at institutions like WashU, this article explores key questions around diagnostics, functional assessments, and whether therapies like Tofersen could revolutionize ALS treatment—not just for SOD1 but potentially for broader ALS populations as well.
FEATURED QUESTIONS:
Are neurofilament levels routinely measured by neurologists in ALS clinics in the U.S., and should neurofilament testing be considered a standard part of ALS patient evaluation?
It’s not a standard of care at the moment. And, here in the neuromuscular lab under Dr. Robert Bucelli, we have been measuring serum neurofilament since 2021, and most of the attendings here have adopted it as a relatively good biomarker to use when patients come in for evaluation of ALS. There are some caveats, as it may not be elevated in all patients. And, so, it’s not a single test to be able to confirm ALS diagnosis. It needs to be taken in the context of the clinical exam, the clinical history of progression of weakness, excluding other diagnoses that can mimic ALS. I strongly advocate for testing for all my patients in the initial stages, as well during long-term follow-up as well.
Has there been any instance of a person with genetic forms of ALS, such as SOD1 or FUS mutations, who lost the ability to speak and then regained speech following successful treatment?
Not that I am aware of. None of our patients have significant speech changes. Some of the research studies conducted by EverythingALS highlight speech changes and I think some of the recent trials are including software or applications to do that. We haven’t heard of any patient living with ALS with an SOD1 gene receiving Tofersen with chewing or swallowing issues. Some with respiratory issues include the need to be on non-invasive ventilation. This might not be a fair comparison, considering representation of the whole ALS population, but following the data, there are definite possibilities to improve functioning in patients living with ALS undergoing disease stabilization therapy.
What do you make of the recent data published from various Italian EAPs?
While I am not familiar with this publication, there are several studies cited in our research papers that showed similar results of Tofersen in the clinical setting or real-world setting, which depicts significant reduction in the neurofilament levels, maintenance of function, with some patients potentially having continued progression at a slower rate, and some patients showing improvement. Nearly 20-25% of the patients show some degree of improvement. It is to be noted that all of our patients living with ALS have elevated inflammatory attributes (factors) in the spinal fluid. There is no clinical correlation for this, and there are no patients who have experienced severe side effects due to Tofersen. These include increased intracranial pressure, increase in the spinal fluid, radiculitis, or inflammation of the nerves or spinal cord.
When standardized (e.g., converted to Z-scores), do functional outcome measures like the ALSFRS-R and FIM show consistent effect sizes post-Tofersen treatment?
Yes. The sample size of participants was very small, estimated to be around 7. We lacked longitudinal data for one of the participants to report on. The studies were oriented to descriptive statistics over inferential statistics, implying that we are trying to present the data collected over making comparisons. So, FIM, as in functional independence motor score, has been leveraged in several ALS research studies. There is a correlation between FIM motor score and a decline in the ALSFRS overtime with disease progression. It has not been used to monitor for functional improvement in patients living with ALS undergoing disease stabilizing therapies. We are the first paper to present the possibility of using this as a measure in comparison to ALSFRS, and it seems to be more sensitive to patient improvement and functional independence than ALSFRS. The focus as a team is to conduct a larger study with funding.
I have SOD1 but no one in my family has ALS disease. It is interesting that 6 out of 7 in the study similarly had no family member with ALS. Can you explain why, since I was told by the genetic counselor that the mutation is dominant?
Yes, it is interesting that 6 out of 7 had no clear family history of ALS. The majority of the mutations in SOD1 are dominantly inherited. At some point, without a family history, it’s possible for an individual to be the first to develop the mutation. So, there is not much clarity as to why an individual would develop that specific mutation in SOD1. However, we are going to continue to learn more about genetics. The study we conducted highlights the potential of differential response, based on the type of genetic mutation. This highlights a need within ALS research to better identify which patients may or may not benefit from Tofersen, or may not need additional treatment options to fully stabilize their disease.
Given increased cardiovascular risk in ALS disease, how does your program take these risks into account, specifically the maximum heart rate to determine the exercise targets.
Typically, our programs start relatively conservatively and we use low-to-moderate intensity. Presently, the neuromuscular literature indicates between 50 – 70% of the heart rate reserve. Heart rate reserve is a calculation which is based on the individual’s resting heart rate and age, which generates an individualized baseline. We will start by using 50-70% of that maximum and also use the rate of perceived exertion. For individuals with higher respiratory involvement, we have a breathlessness scale for self-monitoring. Furthermore, there are continuous heart rate and oxygen monitors when capacity is measured. During the 10m walk and the 30 seconds sit-to-stand test, we are also monitoring physiologic response and administering a dose based on the tolerance levels, but in general, we have been starting folks conservatively in the 50-70% range. However,individuals have also progressed to the moderate-vigorous range (70-85%). Generally, we use the cardio or heart rate response as a gauge of neuroplasticity and neuromuscular control.
In the context of ALS clinical assessments which you shared, when performing the 10-Meter Walk Test (10mWT), is the test typically conducted with the participant wearing their orthotic devices, or without them?
Yeah, we have done a measure for both. It depends on the individual, and we try to make it a day-to-day activity in their real life. For the patients living with ALS wearing their orthotic devices, I highly encourage them and mention the same in prescriptions for improved safety and control. All the measures are a great gauge, but they are typically capacity measures. It helps us get a baseline, get a measure, help prescribe the activity, discuss safety recommendations such as orthotics, wear, and use. But, one area that can be specifically improved is getting performance measures and tracking activity outside of therapy to understand how the rehab is influencing those individuals outside of the measures we are seeing right in front of us.
What are the broader implications for other forms of ALS outside of SOD1? What is the perspective concerning drug development care paradigms as well as rehabilitation programs?
It’s kind of limited right now. There’s a minimal amount of information on how to do neuron muscle rehab for a patient with ALS whose disease has stabilized. The goal is for multiple drugs or treatments to be made available to help any patient with any form of ALS to reach disease stabilization. At that point, the question is how can we get the function back? I think it’s going to take a lot more than only treatment for patients to have recovery and live with ALS. And, so, we are building the foundational knowledge of what that would look like. It’s a pretty decent step in the right direction that patients on a disease stabilizing treatment like Tofersen right now can participate in neuromuscular rehab for extended periods of time and do it safely. We can progress them, whether that is through resistance exercise with different weights, or increasing their walking program using technology available to help mobility. There is a definite need for extensive research on this subject and hopefully when substantial treatment is available, we can implement the knowledge for patients living with ALS rather than waiting.
When we look at the biggest body of evidence right now within neuromuscular rehab, it’s typically within stroke rehab. We are observing that, with the right dosage of therapy, when patients are in a medically stable position, high intensity rehab can be greatly effective in improving motor function, even years after the initial stroke. This model gives us hope that we can change the current model from low-to-moderate, shifting focus from maintenance in ALS disease management to neuroplasticity and improvement of function.
During the sit-to-stand test in your protocols, is the use of arms to assist in pushing oneself up from the chair allowed or expected?
The standardized assessment is without upper arm assistance. However, there are some patients living with ALS who are unable to perform that, so we allow them to use arm assistance because that is expected as a means to get out of the chair for long-term, based on their current status.
Are the patients in your study just those who go to WashU’s clinic or do you get data from other hospitals (eg. Mass General Hospital)?
Presently, it is an internal study of patients only at WashU who recurrently follow-up in our clinic and are receiving the Tofersen dosing here. It’s unfunded right now. The ALS center and a bunch of other individuals who are highly devoted to seeing patients improve are actively working on the study. Our work with the patients is very goal-oriented and is focused on their routine activities, and we would like to expand this approach. We have submitted some grants to that end and we are still waiting for funding opportunities in the near future.
What was the time between first and second measurements of function?
With reference to the FIM score, we have been keeping all the functional measures for those we have been taking out on a monthly basis. The other ones shown in the slides with the graph consisted of the most recent Tofersen dose, and varied for all the patients over time. For instance, one patient living with ALS was on Tofersen for over 7 months and his FIM score improved from 86 to 89. Another patient living with ALS was on Tofersen for 30 months and had improvement from 86 to 89. So, we are seeing it in the short-term as well as analyzing the functional gains that are retained for a significant period of time.
I'm pre-symptomatic SOD1 L145F variant, which excluded my participation in ATLAS. Back when ATLAS was rolling out recruitment, I spoke to Dr. Bucelli and he mentioned that WashU was "looking at possibly doing a mirror study" of ATLAS. Are you aware of any recent new discussions of such a study?
Yes. For the unversed, ATLAS is a study in presymptomatic individuals with SOD1 mutations. They have limited the ALS research study for certain variant mutations, that’s what the question was addressed to. When there’s a change in the neurofilament level, when it increases or if an individual becomes asymptomatic with weakness, it’s potentially starting very early Tofersen treatment in the hopes of delaying the onset of ALS disease or even preventing the onset. So, that ALS research study is still ongoing, and we are not yet able to share data publicly. Hopefully, the study will have promising results and there’s potential looking at the broader implications that – the sooner we confirm ALS diagnosis, especially the genetic form or hereditary, ALS treatment can be initiated promptly. During the time when symptoms of ALS start showing up, there could be a possibility that we can prevent the onset of ALS disease, which could be amazing.
I am not aware of any kind of mirror study, but I will definitely pass that along to Dr. Bucelli and let him know about the question.
Why can’t non gene mutation patients be offered the rehabilitation program at their own discretion?
[I wasn’t offered any PT during the first 3 years of a clinic setting but pursued a clinic setting that agreed to let me try! Can this not be a patient/clinic discussion and decision, not a blanket statement? Every good day is a joy, let us have our days]
We actually recommend rehab programs for all of our ALS patients we see. The difference in ALS treatment here is the dosage and how those programs are tailored. There is good evidence for low-to-moderate intensity exercise, but we really recommend working with individuals or therapists familiar with ALS disease progression, because it can be a tough balance to titrate those programs appropriately. There is a risk for muscle overuse and further muscle decline. The biggest thing is, when you are strengthening muscle, it can break down those muscle fibers. In healthy individuals, they typically grow stronger. For patients with ALS that are not on disease stabilizing medications, that poses a risk that we want to monitor. Exercise can still be appropriate, as long as it's dosed well and individualized to that person. Here at WashU, we do work with all of our patients living with ALS, it’s just the difference in the dosage. Basically, making sure the program that is prescribed for the patients is monitored and changed over time. We have individuals that come in monthly, 3 months, 6 months, or other frequencies to ensure that the program that they have been given is tailored to their needs. Ultimately, the ALS treatment approach is goal-oriented, and it’s personalized to what they want to be able to do, with the goal of enhancing their quality of life.
Do you have exercise programs for patients with ALS at different stages and fitness levels? What are recommendations for patients who don’t have access to your clinic?
Yeah, a really good resource, free for clinicians and patients is the Academy of Neurologic Physical Therapy. It’s all neurologic-specialized physical therapists, and so there is literature and evidence-based practices for guidelines on low-to-moderate exercise. I still highly recommend working with a therapist who specializes in ALS so that they can test and measure patients with ALS for their functional capacity. There’s also another website called ‘Choose PT’ where you can search for a physical therapist who specializes in ALS in your area
Do you see Toferson being used prophylactically?
The ALS research study conducted by ATLAS is hoping to answer whether it is possible to treat someone who has not yet developed the symptoms of ALS but has increased levels of neurofilament, and if so, to understand the potential clinical benefits. After the completion of the study, it will give us a lot more information on how to best use Tofersen in treatment of SOD1 ALS. There’s also some interesting research in sporadic ALS that SOD1 protein misfolds and contributes to the pathology of ALS. It would be interesting to study the use of Tofersen in non-SOD1 ALS patients and look for any prevalent benefits.
CONCLUSION:
The growing clinical research studies around Tofersen and neuromuscular rehabilitation is signaling a critical shift in ALS treatment options. From proactive biomarker testing like neurofilament levels to individualized exercise protocols, care is becoming more patient-centered and precision-driven. While genetic therapies like Tofersen are currently specific to SOD1 ALS, the insights gained are paving the way for broader applications. The future of ALS treatment may lie in early detection, personalized rehab, and a multidisciplinary approach that combines medical and functional care. With continued research and collaborative innovation, there’s real hope for improved quality of life and recovery potential in patients living with ALS.
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