A year ago, a new study drew attention because it was a "hopeful anomaly." It challenged the fatalistic narrative of ALS and provided a clear, new direction for this research field. The ALS therapeutic landscape has seen many failures. Most drugs only slow the disease slightly. For those living with ALS, this study was a concrete reason for hope.
The idea that the secrets to curing the disease might be found in rare individuals who mysteriously recover is a compelling story. It suggests that the biological processes of ALS aren't always one-way and that recovery, though rare, might be possible.
Now, some readers have published a response to this study.
It's behind a paywall, so I haven’t read it, but I can guess what it says. Additionally, a recent publication states: "variants in IGFBP7 were linked to rare "ALS reversals," but the existence of such cases remains controversial." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/
In the study published last year, researchers told that they gathered 22 documented reversal cases and validated them across the Target ALS database. This was a pilot case-control study at Duke ALS Clinic in Durham, North Carolina.
The investigators collected demographics, disease details, pedigree info, and saliva samples from ALS reversals. Whole-genome DNA was extracted and sequenced from these saliva samples. The genomes of ALS reversals were then compared to previous whole-genome sequences from a biorepository of de-identified samples of more typical ALS patients. https://clinicaltrials.gov/study/NCT03464903
The researcher has confirmed 34 of these "reversal" cases so far by reviewing medical records. These patients differ in demographics and disease features compared to typical ALS patients. One possible explanation is that these individuals are genetically different, granting them a form of disease "resistance".
However, it appears that cases of ALS reversal are primarily documented in this specialized clinic. This does not mean that such cases do not exist elsewhere, but the diagnosis of ALS and, therefore, of ALS reversal is complicated. For example, it differs between countries in Europe, the United States, and Asia. More importantly, diagnoses vary considerably among doctors.
The problem is that we don’t fully understand what ALS is. Most agree it’s a phenotype that can result from many different causes—some genetic, others from exposure to neurotoxins, physical injury, or other factors.
An example of these variations in practice: the clinical study manager accepted people with primary muscular atrophy (PMA) into his study but PMA is not ALS.
Another issue is how to define “reversal.” Here, reversal was defined as an improvement of at least 4 points on the ALS Functional Rating Scale, maintained for at least 6 months. The ALSFRS-R scale is known to be flawed; it can show improvement simply because of the use of new assistive devices. A 2016 paper co-authored by this researcher stated that most of these “plateaus” and “reversals” are temporary: "ALS plateaus and small reversals are common, especially over brief intervals." https://pubmed.ncbi.nlm.nih.gov/26658909/
The new publication also states: "It is not yet clear if extremely rare “ALS reversals” suffer from typical ALS, or rather from another, yet undescribed disease mimicking ALS diagnostic criteria." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/
The last year's study didn't just describe the phenomenon; it identified a specific gene, IGFBP7. It linked reversals to a noncoding variant near IGFBP7, which influences IGF-1 receptor activity. Since IGF-1 has long been suspected of having neuroprotective effects (it has been tested in past ALS clinical trials), this genetic link feels biologically plausible. Yet, more than one hundred genes are associated with ALS, especially SOD1, FUS, and C9orf72 (~9% of cases). These genes aren’t directly related to IGF, making it hard to think that patients with mutations in those genes could still experience reversals.
The authors did openly acknowledge the study’s limitations, which likely sparked discussion:
- The "Reversal" group included only 22 participants. This is a major limitation, and the results must be confirmed with larger groups.
- The study shows a strong genetic link, but it doesn’t prove that the IGFBP7 variant causes the reversals. It seems Professor Bedlack is now exploring this path: https://pubmed.ncbi.nlm.nih.gov/40944442/