In collaboration with Dr. Rick Bedlack, ALS TDI researchers were able to rapidly conduct an in-depth analysis of a potential new avenue for ALS research using data from the ARC study.

On Wednesday, November 6th, the ALS Therapy Development Institute (ALS TDI) hosted a town hall to discuss the findings of a study investigating the role of a protein of interest, IGFBP7, in ALS. The event featured presentations from Dr. Fernando Vieira, ALS TDI’s CEO and Chief Scientific Officer, as well as Dr. Rick Bedlack, Director of the Duke ALS Clinic. The study is the result of an ongoing collaboration between Dr. Bedlack and ALS TDI’s ALS Research Collaborative (ARC) team to investigate extremely rare cases of ALS reversals.

What is an ALS Reversal?

In nearly all cases of ALS, the disease progresses from early, more mild symptoms of muscle weakness, toward increasing paralysis, leading eventually to death. In an ALS reversal, however, a person is diagnosed with ALS, progresses for a time, and then improves.

ALS reversals have been described in the literature by many different neurologists, starting in the 1960s. Dr. Bedlack has been collecting, verifying and studying these cases with different collaborators for over 10 years

Collaborating to Learn More about ALS Reversals

In 2021, ALS TDI and Dr. Bedlack announced a partnership to investigate what might be behind ALS reversals and if they could teach us about possible avenues for treating other cases of ALS. Several people identified by Dr. Bedlack as having undergone reversals were enrolled in ALS TDI’s ALS Research Collaborative (ARC)Study – a natural history study in which people with ALS can contribute data about their disease to help support ALS research. Through ARC, people with ALS are able to submit data including medical history, demographic information, and blood samples.

In a separate collaboration with the CReATe Consortium (https://create.rarediseasesnetwork.org), to investigate possible genetic factors that could be related to ALS reversals, Dr. Bedlack and colleagues conducted whole genome sequencing of samples from 22 ALS reversals. In comparing the sequencing results to larger databases of people with ALS, Dr. Bedlack’s team identified a genetic variant that appeared to be significantly more common in ALS reversals than ethnicity matched controls from 2 different databases. The identified variant appeared to regulate the amount of a protein called IGFBP7 in the brain. This finding led to the first plausible explanation for how someone could recover from ALS. 

Investigating IGFBP7

After Dr. Bedlack brought these findings to his collaborators at ALS TDI, the ARC team decided to look into the potential role of this mutation and the protein it affects (IGFBP7) in ALS. To do this, they consulted a dataset generated from a Department of Defense-funded project to analyze the levels of 7500 different proteins in blood samples collected through ARC.

Their analysis indicated some intriguing trends that they believe warranted further investigation. To continue exploring this line of inquiry, ARC researchers developed anassay (or test) that could measure the levels of the IGFBP7 protein in the blood. Over three months, they tested more than 200 total blood samples from 51 ARC participants, as well as 10 healthy controls. Finally, they performed the assay on blood samples provided by 11 people enrolled in ARC who had been designated ALS reversals by Dr. Bedlack.

IGFBP7 Study Results

The team began the study based on Dr. Bedlack’s hypothesis that, if IGFBP7 played a significant role in reversals, people with ALS reversals would have lower levels of IGFBP7 in their blood.

Looking at the results of these studies on IGFBP7, the ARC team found that:

  • Blood levels of the IGFBP7 protein were statistically significantly higher in people with ALS than in healthy controls.
  • Levels of IGFBP7 were not statistically different in ALS reversals compared to controls with ALS that had not reversed, nor in those patients who had the genetic variant of interest versus those that did not have it
  • No relationship was found between IGFBP7 levels and ALS progression rate

Whole genome sequencing data from ARC Study participants indicated that some people with ALS, with various rates of disease progression, were positive for either one copy or two copies of the rs4242007 IGFBP7 variant.

Overall, the results did not support the hypothesis that lower levels of IGFBP7 in blood were correlated to slower ALS or ALS reversals.

Next Steps

The results of this study, according to the interpretation of the ALS TDI team, did not support IGFBP7 as a priority target for new ALS treatments above other targets in our current pipeline. Still, Dr. Vieira said in his presentation, the team will remain receptive to new information about IGFBP7 that may come to light that could change this determination.

Dr. Bedlack, for his part, expressed that the study was not the “home run” he hoped to discover. However, he does believe the results of this study warrant further investigation. In his view, the fact that IGFBP7 protein levels were higher in people with ALS than in healthy controls could support the hypothesis that a mutation affecting the expression of this protein could play a role in ALS reversals. He also suggested that, even though IGFBP7 levels do not appear to influence the speed of progression in people with ALS, the protein could affect resistance to the diseases and the likelihood of experiencing a reversal.

To continue studying the role of IGFBP7 in ALS, Dr. Bedlack is considering conducting a trial targeting the protein in people with ALS. This trial would likely test an already available supplement, HMB, that is known to knock down blood levels of IGBP7. Dr. Bedlack’s ROAR framework – a program that allows for small, fast, and mostly remote studies of supplements as potential ALS treatments.

What Can We Learn From the Study?

Despite not yielding breakthrough results, this study serves as a model for collaboration between ARC Study researchers at ALS TDI and their scientific partners. Looking at data collected through ARC, Dr. Bedlack was able to form an intriguing hypothesis about ALS reversals.

In turn, ARC researchers were able to quickly respond to this finding and, in a matter of months, conduct an in-depth analysis of a potential new avenue for ALS research. Collaborations such as this will continue to be an important part of ALS TDI’s research focus as we pursue our ultimate mission – to find effective treatments for everyone with ALS.

To learn more about this study and ALS TDI’s collaboration with Dr. Rick Bedlack of the Duke ALS Clinic, watch a recording of the ALS Town Hall here.

What to Do Next: